CN114502200A - 抗体药物缀合物 - Google Patents
抗体药物缀合物 Download PDFInfo
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- CN114502200A CN114502200A CN202180005506.XA CN202180005506A CN114502200A CN 114502200 A CN114502200 A CN 114502200A CN 202180005506 A CN202180005506 A CN 202180005506A CN 114502200 A CN114502200 A CN 114502200A
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- Prior art keywords
- compound
- antibody
- cancer
- linker
- amino
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- 239000000611 antibody drug conjugate Substances 0.000 title abstract description 51
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- IEDXPSOJFSVCKU-HOKPPMCLSA-N [4-[[(2S)-5-(carbamoylamino)-2-[[(2S)-2-[6-(2,5-dioxopyrrolidin-1-yl)hexanoylamino]-3-methylbutanoyl]amino]pentanoyl]amino]phenyl]methyl N-[(2S)-1-[[(2S)-1-[[(3R,4S,5S)-1-[(2S)-2-[(1R,2R)-3-[[(1S,2R)-1-hydroxy-1-phenylpropan-2-yl]amino]-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl]-3-methoxy-5-methyl-1-oxoheptan-4-yl]-methylamino]-3-methyl-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]-N-methylcarbamate Chemical compound CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCc1ccc(NC(=O)[C@H](CCCNC(N)=O)NC(=O)[C@@H](NC(=O)CCCCCN2C(=O)CCC2=O)C(C)C)cc1)C(C)C IEDXPSOJFSVCKU-HOKPPMCLSA-N 0.000 claims description 20
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- DLKUYSQUHXBYPB-NSSHGSRYSA-N (2s,4r)-4-[[2-[(1r,3r)-1-acetyloxy-4-methyl-3-[3-methylbutanoyloxymethyl-[(2s,3s)-3-methyl-2-[[(2r)-1-methylpiperidine-2-carbonyl]amino]pentanoyl]amino]pentyl]-1,3-thiazole-4-carbonyl]amino]-2-methyl-5-(4-methylphenyl)pentanoic acid Chemical compound N([C@@H]([C@@H](C)CC)C(=O)N(COC(=O)CC(C)C)[C@H](C[C@@H](OC(C)=O)C=1SC=C(N=1)C(=O)N[C@H](C[C@H](C)C(O)=O)CC=1C=CC(C)=CC=1)C(C)C)C(=O)[C@H]1CCCCN1C DLKUYSQUHXBYPB-NSSHGSRYSA-N 0.000 claims description 11
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- 102000002274 Matrix Metalloproteinases Human genes 0.000 claims description 9
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- 125000003118 aryl group Chemical group 0.000 claims description 8
- VQNATVDKACXKTF-XELLLNAOSA-N duocarmycin Chemical compound COC1=C(OC)C(OC)=C2NC(C(=O)N3C4=CC(=O)C5=C([C@@]64C[C@@H]6C3)C=C(N5)C(=O)OC)=CC2=C1 VQNATVDKACXKTF-XELLLNAOSA-N 0.000 claims description 8
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- DPOPAJRDYZGTIR-UHFFFAOYSA-N Tetrazine Chemical compound C1=CN=NN=N1 DPOPAJRDYZGTIR-UHFFFAOYSA-N 0.000 claims description 7
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Abstract
本文提供了一种抗体药物缀合物(ADC),尤其是通过位点特异性缀合制备的聚乙二醇化单特异性或多特异性抗体药物缀合物(BsADC),以提供具有高效力和低毒性的均质缀合物。还涉及ADC的制备方法、包含ADC的化合物及其在治疗疾病中的用途。
Description
本申请要求于2020年4月15日提交的PCT申请PCT/CN2020/084880的申请日期的权益,该申请的全部内容通过引用并入以用于所有目的。
技术领域
本发明涉及抗体药物缀合物(ADC),尤其涉及通过位点特异性缀合制备的多特异性抗体药物缀合物,以提供具有高效力和低毒性的均质缀合物。特别地,本发明涉及长效的聚乙二醇化单特异性或双特异性单链抗体药物缀合物,其通过聚乙二醇化药物与单特异性或双特异性抗体的位点特异性缀合而制备。
发明背景
癌症治疗一直进展缓慢,从外科手术(19世纪后期)到放射治疗(20世纪初期),从化疗和激素治疗(20世纪中期)到靶向药物(20世纪90年代),以及从靶向药物与化疗和激素的组合(21世纪初期)到最近的抗体药物缀合物(ADC)等。用ADC治疗癌症的概念可以追溯到50多年前(Decarvalho,S.等人,Nature,1964,202,255-258):使用抗体作为载体将极其强效的物质直接递送到肿瘤细胞。早期的ADC使用了本身具有抗原性的非人源化抗体、难以获得和使用的β-发射放射性核素载荷,以及过早释放细胞毒性载荷的非稳定接头。今天的ADC技术使用人源化抗体、高度细胞毒性的有机载荷、以及相对稳定的接头,该接头被设计用于保持细胞杀伤剂的完整性直到到达靶标且整个ADC分子内化到细胞中。
在美国,有10种ADC被FDA批准,其全部用于癌症治疗,目前有100多种ADC候选药物正活跃在临床试验中(Beacon Targeted THerapies的研究报告|hansonwade)。所有十个被批准的ADC在治疗期间都显示出严重的副作用。事实上,10个被批准的ADC中有8个需要携带黑匣子警告标签,这限制了它们在各种癌症适应症中的应用。今天基于IgG的ADC的最大挑战是要求在非常接近最大耐受剂量(MTD)时施用以显示治疗益处,这导致了非常窄的治疗窗口(Beck,A.等人,Nat.Rev.Drug Discov.,2017,16,315-337;Vankemmelbeke,M.等人,THer.Deliv.,2016,7,141-144;TolcHer A.W.等人,Ann.Oncol.,2016,27,2168-2172)。此外,这些ADC上发现的毒性特征与标准护理化疗药物的毒性特征相当,伴有与细胞毒性弹头有关的剂量限制性毒性(Coats,S.等人Clin.Cancer Res.,2019,25,5441-5448)。在临床试验中终止的约80种传统ADC中,大多数终止的原因是与现有疗法相比,治疗窗口或指数不佳。有充分证据表明,缀合的位点和接头/药物的疏水性对ADC的稳定性、功效和治疗指数具有显著影响,并且细胞毒性分子与具有亲水接头的抗体的位点特异性缀合可以提高治疗指数(Junutula,J.R.等人,Nat.Biotechnol.,2008,26,925-932;Lyon,R.P.等人,Nat.Biotechnol.,2015,33,733-735)。然而,目前在临床开发或市场上的许多ADC需要裂解全长抗体的两个或更多个链间二硫键以获得高DAR。不幸的是,该方法可能导致蛋白质的不稳定。对于携带Fc的BsADC而言尤其如此,因为双特异性抗体是非天然的抗体,并且制造具有高DAR的携带Fc的BsADC更加困难。开发中的或已批准的许多其他ADC是通过与抗体的半胱氨酸残基或赖氨酸残基的随机缀合制备的,并且本质上是异质的,这给临床环境中的分析和精确施用带来了困难。而且,由全长抗体构建的ADC分子被认为过大,从而难以深入渗透到致密的实体瘤中以治疗中期到晚期癌症。此外,所有携带Fc的传统ADC都具有内在毒性,这是由于其Fc与巨核细胞(MK)上的FcγRIIa结合并随后内化,然后杀伤巨核细胞,从而最终导致血小板生产的停止和血小板减少症(Uppal,H.等人,Clin Cancer Res;21(1)January 1,2015),并且针对抗体药物缀合物所观察到的的许多脱靶毒性也由与ADC的Fc组分直接相关的甘露糖受体吸收而驱动(Gorovits,B.等人,2013,Cancer ImmunolImmunotHer 62,217-223)。
因此,迫切需要具有增强的效力和改善的毒性特征的新型ADC技术。
发明概述
本发明通过提供非免疫原性聚合物修饰的抗体药物缀合物来解决上述未满足需求,所述抗体药物缀合物通过以下方式制备:通过用于位点特异性缀合的工程化位点(例如半胱氨酸),聚合物修饰的(例如聚乙二醇化的)药物缀合物与单特异性或多特异性抗体片段,或者与单特异性或多特异性单链抗体进行位点特异性缀合。抗体片段或单链抗体针对抗原可以是一价或多价的。
在一方面,本发明提供了式的聚合物抗体药物缀合物分子。P可以是非免疫原性聚合物。T可以是多官能(例如三官能)小分子接头部分,并且具有至少一个能够与单特异性或多特异性抗体或蛋白质位点特异性缀合的官能团。A可以是任何单特异性或多特异性抗体或蛋白质。D可以是任何细胞毒性小分子或肽(n≥1),每个D可以相同或不同。
特别地,本发明的一个方面提供了式Ib的缀合物:
其中:
P可以是非免疫原性聚合物;
M可以是H或选自C1-50烷基和芳基的封端基团,其中所述烷基的一个或多个碳任选地被杂原子取代;
y可以是选自1、2、3、4、5、6、7、8、9和10的整数;
T可以是具有两个或更多个官能团的多官能接头,包括但不限于三官能或四官能或任何其他环状或非环状多官能部分(例如赖氨酸),其中T和(L1)a之间的连接以及T和(L2)b之间的连接可以相同或不同;
L1和L2中的每一个可以独立地是双官能团接头;
a和b各自可以是选自0、1、2、3、4、5、6、7、8、9和10的整数;
B可以是带支链的接头,其中每个支链可包含延伸间隔物、触发单元、自消解间隔物(self-immolating spacer)或其任何组合,其中触发单元可以是氨基酸序列或由酶裂解的触发部分、可以在酸性pH条件下释放药物D或其衍生物的pH敏感接头(pH liablelinker)、或可以通过化学或酶促裂解释放药物D或其衍生物的二硫键接头、或可以通过特定裂解机制释放药物D的可裂解键;
A可以是任何单特异性或多特异性抗体或抗原结合蛋白,包括抗体片段、单链抗体、纳米抗体或任何抗原结合片段,其针对抗原可以是一价或多价的。
D可以是任何细胞毒性小分子或肽或其衍生物,并且可以通过酶促裂解和/或自消解机制(self-immolating mechanism)或者具有或不具有自消解机制的pH诱导的水解从B释放;每个D可以相同或不同;
n可以是选自1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24和25的整数。
本发明的另一方面提供了式Ic的缀合物:
其中每个变量如式Ib所定义。
在一些实施方案中,B的每个支链包含触发部分,例如氨基酸序列或二硫化物部分或β-葡萄糖苷或β-半乳糖胺,其通过自消解间隔物连接到药物D或直接连接到药物D,由例如组织蛋白酶B、纤溶酶、基质金属蛋白酶(MMP)、谷胱甘肽、硫氧还蛋白、硫还原酶裂解(Arunachalam,B.等人,2000,PNAS,97(2)745-750)。自消解间隔物的实例包括但不限于以下:
其中R1、R2、R3、R4可以是H或C1-10烷基。在这样的实施方案中,D可以是含有活性O或N或S官能团的任何小分子或肽或其衍生物。
在一些实施方案中,B的每个支链可以是pH敏感接头,其可以在肿瘤部位和/或肿瘤细胞内部的酸性pH条件下释放药物D或其衍生物。酸性敏感接头(acidic liable linke)的实例包括但不限于以下形式:
-CR1=N-NR1-、-CR1=N-O-、-CR1=N-NR2-CO-、-N=N-CO-、-OCOO-、-NR1-COO-。
在一些实施方案中,B的每个支链可以是二硫键接头,其可以通过化学或酶促裂解在肿瘤部位和/或肿瘤细胞内部释放药物D或其衍生物,该酶促裂解例如为谷胱甘肽、硫氧还蛋白家族成员(WCGH/PCK)或硫还原酶酶促裂解。
在一些实施方案中,A是针对抗原为一价或二价的单特异性抗体,例如针对抗原为一价或二价的单特异性单链抗体。
在一些实施方案中,A是多特异性抗体,例如双特异性单链抗体。
在一些实施方案中,双特异性抗体的两个结合域与两个相同的肿瘤相关抗原(TAA)分子在两个不同的表位结合,或与两个不同的肿瘤相关抗原分子结合。
在另一个实施方案中,A是单链抗Her2 x抗Her2抗体(SCAHer2xSCAHer2),其与癌细胞上表达的Her2结合。SCAHer2xSCAHer2抗体的两个结合域可以与两个Her2分子上的相同表位结合,或与两个Her2分子上的两个不同表位结合。在一些实施方案中,抗体具有如SEQ ID NO:1或SEQ ID NO:2所示的氨基酸序列。
在一些实施方案中,单链抗体的两个结合域通过接头连接,并且其中所述接头可包含例如半胱氨酸或非天然氨基酸残基的部分,以用于抗体与L1的位点特异性缀合。
在一些实施方案中,D可以选自任何DNA交联剂、微管抑制剂、DNA烷化剂、拓扑异构酶抑制剂或其组合。
在一些实施方案中,D可以选自MMAE、MMAF、SN38、DM1、DM4、刺孢毒素(calicheamycin)、吡咯并苯二氮卓类、倍癌霉素(duocarmycin)或其衍生物、或其组合等。
在一些实施方案中,D是单甲基奥瑞他汀E(MMAE,一种抗有丝分裂药物)或其衍生物;或SN38(一种强效拓扑异构酶I抑制剂)或其衍生物;或其组合。
在另一个实施方案中,D是MMAE,并且与例如4-氨基苄醇(PAB)的自消解间隔物以及例如缬氨酸-瓜氨酸的触发部分连接。
在上述任何方面和实施方案中,非免疫原性聚合物可选自聚乙二醇(PEG)、右旋糖酐、碳水化合物聚合物、聚环氧烷、聚乙烯醇、羟丙基甲基丙烯酰胺(HPMA)及其共聚物。优选地,非免疫原性聚合物是聚乙二醇,例如带支链聚乙二醇或直链聚乙二醇。聚乙二醇的总分子重量可以为5000至100,000道尔顿,例如,5000至80,000奥尔顿、10,000至60,000道尔顿以及20,000至40,000道尔顿。聚乙二醇可以通过永久键或可裂解键与多官能部分T连接。
用于形成(L1)a和蛋白A之间连接的位点特异性缀合官能团可以选自硫醇、马来酰亚胺、2-吡啶基二硫代变体、芳族砜或乙烯基砜、丙烯酸酯、溴代或碘代乙酰胺、叠氮化物、炔烃、二苯并环辛基(DBCO)、羰基、2-氨基-苯甲醛或2-氨基-苯乙酮基团、酰肼、肟、酰基三氟硼酸钾、O-氨基甲酰基羟基胺、反式环辛烯、四嗪、三芳基膦、硼酸碘等。
在一些实施方案中,(L1)a中的一种可包含由叠氮化物和炔烃或由马来酰亚胺和硫醇形成的连接。在一些实施方案中,炔烃可以是二苯并环辛基(DBCO)。
在一些实施方案中,T可以是赖氨酸,P可以是聚乙二醇,y可以是1,而炔烃可以是二苯并环辛基(DBCO)。
在一些实施方案中,A可源自叠氮化物标记的单特异性或多特异性抗体或抗原结合蛋白,其包括抗体片段、单链抗体、纳米抗体或其任何抗原结合片段、或其组合,其中叠氮化物可在各自的(L1)a中与炔烃缀合。在另一些实施方案中,A蛋白可源自硫醇标记的单特异性或多特异性抗体或抗原结合蛋白,其包括抗体片段、单链抗体、纳米抗体或其任何抗原结合片段、或其组合,其中硫醇可在各自的(L1)a中与马来酰亚胺缀合。
上述抗体药物缀合物可以根据包括以下步骤的方法制备:(i)制备具有末端官能团的高负荷非免疫原性聚合物药物缀合物,该末端官能团能够与抗体或蛋白质或其修饰形式位点特异性缀合;和(ii)使非免疫原性聚合物药物缀合物与抗体或蛋白质或其修饰结构位点特异性缀合,以形成式Ia、Ib或Ic的化合物。在一些实施例中,可以在缀合步骤之前用小分子接头修饰抗体或蛋白质。
本发明还提供了包含上述抗体药物缀合物的药物制剂,例如对抗原是单价或多价的聚乙二醇化单特异性或双特异性单链抗体药物缀合物,以及药学上可接受的载体。
本发明进一步提供了治疗有需要的受试者的疾病的方法,其包括施用有效量的上述抗体药物缀合物,例如对抗原是单价或多价的聚乙二醇化单特异性或双特异性单链抗体药物缀合物。
本发明的一个或多个实施方案的细节在以下描述中阐述。本发明的其他特征、目的和优点将从附图、描述和权利要求中显而易见。
本公开还提供以下实施方案。
实施方案1.式(Ib)的化合物
其中:
P是非免疫原性的聚合物;
M是H或选自C1-50烷基和芳基的封端基团,其中所述烷基的一个或多个碳可任选地被杂原子取代;
y是选自1至10的整数,例如1至5,例如1、2、3、4、5、6、7、8、9、或10;
A是抗体或其抗原结合片段,以及
T是多官能小分子接头部分;
L1和L2各自独立地是异型或同型双官能接头;
a和b各自是选自0至10的整数,例如0至5,例如0、1、2、3、4、5、6、7、8、9、10;
B是带支链接头,其中每个支链具有与自消解间隔物连接的氨基酸序列或碳水化合物部分,所述氨基酸序列或碳水化合物部分通过酶的裂解触发自消解机制以释放D,或每个支链具有二硫键或可裂解键,所述二硫键或可裂解键的裂解释放D或其衍生物;
D各自独立地是细胞毒性小分子或肽;以及
n可以是选自1至25的整数,例如1至20、1至15、1至10、1至5、5至25、5至20、5至15、5至10、10至25、10至20、10至15、15至25、15至20或者20至25,或者1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25。
实施方案2.实施方案1的化合物,其中T是衍生自具有三个官能团分子的三官能接头,所述官能团选自羟基、氨基、肼基、叠氮化物、烯烃、炔烃、羧基(醛、酮、酯、羧酸、酸酐、酰基卤化物)、硫醇、二硫化物、腈、环氧化物、亚胺、硝基和卤化物,并且其中T和(L1)a之间的连接以及T和(L2)b之间的连接相同或不同。
实施方案3.实施方案2的化合物,其中T是赖氨酸或衍生自赖氨酸。
实施方案4.实施方案1至3中任一项的化合物,其中L1接头末端的官能团能够与A位点特异性缀合,并且选自硫醇、马来酰亚胺、2-吡啶基二硫代变体、芳族砜或乙烯基砜、丙烯酸酯、溴代或碘代乙酰胺、叠氮化物、炔烃、二苯并环辛基(DBCO)、羰基、2-氨基-苯甲醛或2-氨基-苯乙酮基团、酰肼、肟、酰基三氟硼酸钾、O-氨基甲酰基羟基胺、反式环辛烯、四嗪、三芳基膦、硼酸和碘。
实施方案5.实施方案1至4中任一项的化合物,其中所述抗体是单特异性或多特异性全长抗体、单链抗体、纳米抗体或其抗原结合结构域。
实施方案6.实施方案1至5中任一项的化合物,其中所述抗体是单特异性单链抗体。
实施方案7.实施方案6的化合物,其中所述单特异性单链抗体与肿瘤相关抗原(TAA)如Her2结合。
实施方案8.实施方案7的化合物,其中所述单特异性单链抗体具有与Her2结合的两个结合结构域。
实施方案9.实施方案8的化合物,其中所述单特异性单链抗体具有如SEQ ID NO:2所示的氨基酸序列。
实施方案10.实施方案1至5中任一项的化合物,其中所述抗体是双特异性抗体,例如双特异性单链抗体。
实施方案11.实施方案10的化合物,其中所述双特异性抗体的两个结构结合域与相同的肿瘤相关抗原(TAA)结合、与两个不同的TAA结合、或与TAA以及T细胞(例如T细胞受体的组分)或NK细胞上表达的抗原结合。
实施方案12.实施方案11的化合物,其中所述抗体是抗Her2 x抗Her2单链双特异性抗体。
实施方案13.实施方案12的化合物,其中所述抗体具有如SEQ ID NO:1所示的氨基酸序列。
实施方案14.实施方案6至9中任一项的化合物,其中所述单特异性单链抗体的两个结合结构域通过接头连接,并且其中所述接头包含例如半胱氨酸或非天然氨基酸残基的部分用于抗体与L1的位点特异性缀合。
实施方案15.实施方案10至13中任一项的化合物,其中所述双特异性单链抗体的两个结合结构域通过接头连接,并且其中所述接头包含例如半胱氨酸或非天然氨基酸残基的部分用于抗体与L1的位点特异性缀合。
实施方案16.实施方案14至15中任一项的化合物,其中所述非天然氨基酸选自基因编码的烯烃赖氨酸(如N6-(己-5-烯酰基)-L-赖氨酸)、2-氨基-8-氧代壬酸、间或对-乙酰苯丙氨酸、含有β-二酮侧链的氨基酸(如2-氨基-3-(4-(3-氧代丁酰基)苯基)丙酸)、(S)-2-氨基-6-(((1R,2R)-2-叠氮环戊氧基)羰基氨基)己酸、叠氮高丙氨酸、吡咯-赖氨酸类似物N6-((丙-2-炔-1-氧基)羰基)-L-赖氨酸、(S)-2-氨基-6-戊-4-氨基己酸、(S)-2-氨基-6-((丙-2-炔氧基)羰基氨基)己酸、(S)-2-氨基-6-((2-叠氮乙氧基)羰基氨基)己酸、p-叠氮苯丙氨酸、对叠氮苯丙氨酸、Nε-丙烯酰-1-赖氨酸、Nε-5-降冰片烯-2-氧基羰基-1-赖氨酸、N-ε-(环辛-2-炔-1-氧基)羰基)-L-赖氨酸、N-ε-(2-(环辛-2-炔-1-氧基)乙基)羰基-L-赖氨酸、基因编码的四嗪氨基酸(如4-(6-甲基-s-四嗪-3-基)氨基苯丙氨酸)。
实施方案17.实施方案1至16中任一项的化合物,其中D选自DNA交联剂、微管抑制剂、DNA烷化剂、拓扑异构酶抑制剂或其组合。
实施方案18.实施方案17的化合物,其中D选自MMAE、MMAF、SN38、DM1、DM4、刺孢毒素、吡咯并苯二氮卓类、倍癌霉素或其衍生物、或其组合。
实施方案19.实施方案17的化合物,其中D选自长春花生物碱、laulimalide、紫杉烷、秋水仙碱、微管溶素(tubulysin)、念珠藻素(Cryptophycin)、哈米特林(Hemiasterlin)、西马多丁(Cemadotin)、根霉素(Rhizoxin)、圆皮海绵内酯(Discodermolide)、根薯酮内酯(taccalonolide)A或B或AF或AJ、根薯酮内酯AI-环氧化物、CA-4、埃博霉素A和B、laulimalide、紫杉醇、多西他赛、阿霉素、喜树碱、iSGD-1882、centanamycin、PNU-159682、uncialamycin、吲哚并苯二氮卓二聚体、β-鹅膏蕈碱、毒伞毒素(Amatoxin)、泰兰斯他汀类(thailanstatin)或其衍生物或类似物,或其组合。
实施方案20.实施方案1至19中任一项的化合物,其中所述非免疫原性聚合物是聚乙二醇(PEG)。
实施方案21.实施方案20的化合物,其中所述聚乙二醇是直链聚乙二醇或带支链的聚乙二醇。
实施方案22.实施方案20至21中任一项的化合物,其中所述聚乙二醇的至少一个末端用甲基或低分子量烷基封端。
实施方案23.实施方案20至22中任一项的化合物,其中所述聚乙二醇的总分子量为100至80000。
实施方案24.实施方案20至23中任一项的化合物,其中所述聚乙二醇通过永久键或可裂解键与三官能或四官能或任何其他环状或非环状或非环状多官能部分T(例如赖氨酸)连接。
实施方案25.式(Ic)的化合物
其中:
P是直链聚乙二醇;
A是抗体或其抗原结合片段;
L1和L2各自独立地是双官能接头;
a和b各自是选自0至10的整数,例如0至5,例如0、1、2、3、4、5、6、7、8、9、10;
B是带支链接头,其中每个支链具有与自消解间隔物连接的氨基酸序列或碳水化合物部分,所述氨基酸序列或碳水化合物部分通过酶的裂解触发自消解机制以释放D,或每个支链具有二硫键或可裂解键,所述二硫键或可裂解键的裂解释放D或其衍生物;
D各自独立地是细胞毒性小分子或肽;
n是选自1至25的整数,例如1至20、1至15、1至10、1至5、5至25、5至20、5至15、5至10、10至25、10至20、10至15、15至25、15至20或者20至25,或者1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25。
实施方案26.实施方案25的化合物,其中L1接头末端的官能团能够与A位点特异性缀合,并且选自硫醇、马来酰亚胺、2-吡啶基二硫代变体、芳族砜或乙烯基砜、丙烯酸酯、溴代或碘代乙酰胺、叠氮化物、炔烃、二苯并环辛基(DBCO)、羰基、2-氨基-苯甲醛或2-氨基-苯乙酮基团、酰肼、肟、酰基三氟硼酸钾、O-氨基甲酰基羟基胺、反式环辛烯、四嗪、三芳基膦、硼酸和碘。
实施方案27.实施方案25至26中任一项的化合物,其中所述抗体是单特异性或多特异性全长抗体、单链抗体、纳米抗体或其抗原结合结构域。
实施方案28.实施方案27的化合物,其中所述抗体是单特异性单链抗体,任选地,所述单特异性单链抗体与肿瘤相关抗原(TAA)如Her2结合。
实施方案29.实施方案28的化合物,其中所述单特异性单链抗体具有与Her2结合的两个结合结构域。
实施方案30.实施方案29的化合物,其中所述单特异性单链抗体具有如SEQ IDNO:2所示的氨基酸序列。
实施方案31.实施方案27的化合物,其中所述抗体是双特异性抗体,例如双特异性单链抗体。
实施方案32.实施方案31的化合物,其中所述双特异性抗体的两个结合结构域与相同的肿瘤相关抗原(TAA)结合、与两个不同的TAA结合、或与TAA以及T细胞(例如T细胞受体的组分)或NK细胞上表达的抗原结合。
实施方案33.实施方案32的化合物,其中所述抗体是抗Her2 x抗Her2单链双特异性抗体。
实施方案34.实施方案33的化合物,其中所述抗体具有如SEQ ID NO:1所示的氨基酸序列。
实施方案35.实施方案28至30中任一项的化合物,其中所述单特异性单链抗体的两个结合结构域通过接头连接,并且其中所述接头包含例如半胱氨酸或非天然氨基酸残基的部分用于抗体与L1的位点特异性缀合。
实施方案36.实施方案31至34中任一项的化合物,其中所述双特异性单链抗体的两个结合结构域通过接头连接,并且其中所述接头包含例如半胱氨酸或非天然氨基酸残基的部分用于抗体与L1的位点特异性缀合。
实施方案37.实施方案35至36中任一项的化合物,其中用于抗体与L1的位点特异性缀合的非天然氨基酸选残基自基因编码的烯烃赖氨酸(如N6-(己-5-烯酰基)-L-赖氨酸)、2-氨基-8-氧代壬酸、间或对-乙酰苯丙氨酸、含有β-二酮侧链的氨基酸(如2-氨基-3-(4-(3-氧代丁酰基)苯基)丙酸)、(S)-2-氨基-6-(((1R,2R)-2-叠氮环戊氧基)羰基氨基)己酸、叠氮高丙氨酸、吡咯-赖氨酸类似物N6-((丙-2-炔-1-氧基)羰基)-L-赖氨酸、(S)-2-氨基-6-戊-4-氨基己酸、(S)-2-氨基-6-((丙-2-炔氧基)羰基氨基)己酸、(S)-2-氨基-6-((2-叠氮乙氧基)羰基氨基)己酸、p-叠氮苯丙氨酸、对叠氮苯丙氨酸、Nε-丙烯酰-1-赖氨酸、Nε-5-降冰片烯-2-氧基羰基-1-赖氨酸、N-ε-(环辛-2-炔-1-氧基)羰基)-L-赖氨酸、N-ε-(2-(环辛-2-炔-1-氧基)乙基)羰基-L-赖氨酸、基因编码的四嗪氨基酸(如4-(6-甲基-s-四嗪-3-基)氨基苯丙氨酸)。
实施方案38.实施方案25至37中任一项的化合物,其中D选自DNA交联剂、微管抑制剂、DNA烷化剂、拓扑异构酶抑制剂或其组合。
实施方案39.实施方案38的任一项化合物,其中D选自MMAE、MMAF、SN38、DM1、DM4、刺孢毒素、吡咯并苯二氮卓类、倍癌霉素或其衍生物、或其组合。
实施方案40.实施方案38的任一项化合物,其中D选自长春花生物碱、laulimalide、紫杉烷、秋水仙碱、微管溶素(tubulysin)、念珠藻素(Cryptophycin)、哈米特林(Hemiasterlin)、西马多丁(Cemadotin)、根霉素(Rhizoxin)、圆皮海绵内酯(Discodermolide)、根薯酮内酯(taccalonolide)A或B或AF或AJ、根薯酮内酯AI-环氧化物、CA-4、埃博霉素A和B、laulimalide、紫杉醇、多西他赛、阿霉素、喜树碱、iSGD-1882、centanamycin、PNU-159682、uncialamycin、吲哚并苯二氮卓二聚体、β-鹅膏蕈碱、毒伞毒素(Amatoxin)、泰兰斯他汀类(thailanstatin)或其衍生物或类似物,或其组合。
实施方案41.实施方案25至40中任一项的化合物,其中所述聚乙二醇的总分子量为100至80000。
实施方案42.实施方案1至41中任一项的化合物,其中L1和L2各自独立地选自:
-(CH2)aXY(CH2)b-,
-X(CH2)aO(CH2CH2O)c(CH2)bY-,
-(CH2)a杂环基-,
-(CH2)aX-,
-X(CH2)aY-,
-W1-(CH2)aC(O)NR1(CH2)bO(CH2CH2O)c(CH2)dC(O)-,
-C(O)(CH2)aO(CH2CH2O)b(CH2)cW2C(O)(CH2)dNR1-,
-W3-(CH2)aC(O)NR1(CH2)bO(CH2CH2O)c(CH2)dW2C(O)(CH2)eC(O)-,
其中a,b,c,d和e为各自独立地为选自0至25的整数,例如,0至20、0至15、0至10、0至5、5至25、5至20、5至15、5至10、10至25、10至20、10至15、15至25、15至20或20至25,例如0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25;X和Y各自独立地选自C(=O)、NR1、S、O、CR2R3或无;R1和R2独立地代表氢、C1-10烷基或(CH2)1-10C(=O);W1和/或W3衍生自基于马来酰亚胺基的部分,W2代表含三唑基或四唑基的基团;杂环基选自马来酰亚胺基衍生的部分或基于四唑基或基于三唑基的部分。
实施方案43.实施方案1至41中任一项的化合物,其中L1和L2各自独立地选自:
其中n和m是整数,并且独立地选自0至20,例如0至15、0至10、0至5、5至20、5至15、5至10、10至20、10至15或者15至20,例如0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20。
实施方案44.实施方案1至43中任一项的化合物,其中所述带支链接头B包含延伸间隔物、触发单元、自消解间隔物或其任何组合,任选地,其中触发单元是可由酶裂解的氨基酸序列或β-葡萄糖苷酸或β-半乳糖苷触发部分,所述酶例如为组织蛋白酶B、纤溶酶、基质金属蛋白酶(MMP)、β-葡萄糖醛酸酶、β-半乳糖苷酶;可在酸性pH条件下释放药物D或其衍生物的pH敏感接头;或可通过谷胱甘肽、硫氧还蛋白家族成员(WCGH/PCK)或硫还原酶释放药物D或其衍生物的二硫键接头。
实施方案45.实施方案44的化合物,其中带支链接头B选自
其中:
a,b,c,d,e和f各自是整数,并且独立地选自1至25,例如1至20、1至15、1至10、1至5、5至25、5至20、5至15、5至10、10至25、10至20、10至15、15至25、15至20或者20至25,或者1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25;
(A)n是氨基酸序列触发单元,例如Val-Cit、al-Ala、Val-Lys、Phe-Lys、Phe-Cit、Phe-Arg、Phe-Ala、Ala-Lys、Leu-Cit、Ile-Cit、Trp-Cit、D-Phe-LPhe-Lys、Phe-Phe-Lys、D-Phe-Phe-Lys、Gly-Phe-Lys、Gly-Phe-Leu-Gly、或Ala-Leu-Ala-Leu;
PAB是对氨基苄醇;
Ex各自是包含接头链的延伸间隔物,其独立地选自:
-NR1(CH2)xO(CH2CH2O)y(CH2)zC(O)-,
-C(O)(CH2)xNR1-,
-NR1(CH2)xO(CH2CH2O)y(CH2)zNR2-,
-NR1(CH2)xNR2-,
-NR1(CH2)xO(CH2CH2O)y(CH2)zO-,
-O(CH2)xNR1-,
-C(O)(CH2)xO-,
-O(CH2)xO(CH2CH2O)y(CH2)zC(O)-,
-C(O)(CH2)xO(CH2CH2O)y(CH2)zC(O)-,
-C(O)(CH2)xC(O)-,
或无,
其中x,y和z各自是整数,并且独立地选自0至25,例如0至20、0至15、0至10、0至5、5至25、5至20、5至15、5至10、10至25、10至20、10至15、15至25、15至20或者20至25,或者0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25;R1和R2独立地代表氢或者C1-10烷基。
实施方案46.实施方案1至43中的任一化合物,其中所述带支链接头B选自
实施方案47.实施方案1的化合物,其选自下式:
或其药学上可接受的盐。
实施方案48.实施方案25的化合物,其选自式:
实施方案49.制备实施方案1至48中任一项的化合物的方法,其包括:
a)制备具有非免疫原性修饰的(例如聚乙二醇化的)药物缀合物的步骤,所述药物缀合物具有用于位点特异性缀合的游离官能团;
b)将非免疫原性修饰(例如聚乙二醇化的)药物缀合物与抗体进行位点特异性缀合以提供式(Ib)或(Ic)的化合物的步骤。
实施方案50.药物制剂,其包含有效量的实施方案1至48中任一项的化合物和药学上可接受的盐、载体或赋形剂。
实施方案51.实施方案1至48中任一项的化合物,其用于治疗癌症,所述癌症选自乳腺癌、卵巢癌、前列腺癌、肺癌、胰腺癌、肾癌、膀胱癌、胃癌、结肠癌、结直肠癌、唾液腺癌、甲状腺癌和子宫内膜癌。
实施方案52.实施方案1至48中任一项的化合物,其与有效量的另一种抗癌剂、免疫抑制剂组合用于治疗癌症,所述癌症选自乳腺癌、卵巢癌、前列腺癌、肺癌、胰腺癌、肾癌、膀胱癌、胃癌、结肠癌、结直肠癌、唾液腺癌、甲状腺癌和子宫内膜癌。
附图说明
图1示意性地说明了制备实施例1中描述的带支链接头中间体化合物7的反应方案。
图2示意性地说明了制备实施例1中描述的化合物14Val-Cit-PAB-MMAE的反应方案。
图3示意性地说明了制备实施例1中描述的化合物1930kmPEG-Lys(Mal)-(Val-Cit-PAB-MMAE)4的反应方案。
图4示意性地说明了制备实施例3中描述的化合物2030kmPEG-Lys(SCAHer2/SCAHer2)-(Val-Cit-PAB-MMAE)4的反应方案。
图5示意性地说明了制备实施例4中的化合物7 Val-Cit-PABC-MMAE的反应方案。
图6示意性地说明了制备实施例5中的化合物13(具有2XMMAE的带支链接头B)的反应方案。
图7示意性地说明了制备实施例6中的化合物18(具有2XMMAE的带支链接头B)的反应方案。
图8示意性地说明了制备实施例7中的化合物22(具有4XMMAE的带支链接头B)的反应方案。
图9示意性地说明了制备实施例8中的化合物27(具有4XMMAE的带支链接头B)的反应方案。
图10示意性地说明了制备实施例9中的化合物32(30kmPEG(马来酰亚胺)-2MMAE)的反应方案。
图11示意性地说明了制备实施例10中的化合物35(20kmPEG(马来酰亚胺)-4MMAE)的反应方案。
图12示意性地说明了制备实施例11中的化合物39(马来酰亚胺-20mPEG-4MMAE)的反应方案。
图13示意性地说明了制备实施例12中的化合物41(DBCO-20mPEG-4MMAE)的反应方案。
图14显示了实施例13中纯化的化合物42(SCAHer2II×SCAHer2IV)的SDS-PAGE和SEC-HPLC分析。
图15示意性地说明了制备实施例14中的化合物43[30kmPEG-(SCAHer2II/SCAHer2IV)-2MMAE]的反应方案和SDS-PAGE分析。
图16示意性地说明了制备实施例15中的化合物44[SCAHer2II/SCAHer2IV-20kPEG-4MMAE]的反应方案和SDS-PAGE分析。
图17说明了在实施例16中,化合物43(JY201)具有有效的体外细胞毒性。
图18说明了在实施例16中,化合物44(JY201b)在相等载荷下比T-DM1更有效地诱导对肿瘤细胞的体外细胞毒性。
图19说明了在实施例14中,聚乙二醇化BsADC 43(JY201)显示出增加的靶细胞内化。
图20说明了在实施例15中,聚乙二醇化BsADC 43(JY201)在内化后存留在靶细胞中。
图21说明了在实施例16中,聚乙二醇化BsADC 43(JY201)对巨核细胞没有毒性。
发明详述
在本发明中,提供了聚乙二醇化的单特异性或多特异性抗体药物缀合物。根据本发明,不需要破坏抗体的两个或更多个二硫键以获得高DAR,并且可以实现均质的ADC,其在毒性、功效、调控管理和制造方面,特别是在多特异性ADC的制造方面,相较于异质ADC具有显著优势。
此外,本发明提供了聚乙二醇化单特异性或双特异性单链抗体药物缀合物的新颖结构形式,其不仅对巨核细胞或其他正常细胞没有显示出毒性,并且增加了治疗窗口,而且还通过增加的内化增强了缀合物的抗肿瘤作用,并且具有相对小尺寸的单链抗体分子以实现对实体瘤的深度渗透。因此,本发明解决了当前ADC技术中的问题,并通过新型聚乙二醇化单特异性或多特异性单链抗体药物缀合物改善了癌症治疗。
I.缀合物
在本发明的一个方面,提供了式(Ia)的化合物:
在该化合物中,P可以是非免疫原性聚合物。T可以是多官能部分,例如三官能小分子接头部分,并且具有至少一个能够与抗体或蛋白质位点特异性缀合的官能团。A可以是任何单特异性或多特异性抗体或蛋白,例如全长抗体、单链抗体、纳米抗体或其任何抗原结合片段,或其组合。D可以是任何细胞毒性小分子或肽(n=1至25),每个D可以相同或不同。
特别地,本发明的一个方面提供了式Ib或Ic的缀合物:
在式Ib或式Ic的缀合物中,P可以是非免疫原性聚合物,例如聚乙二醇;
M可以是H或选自C1-50烷基和芳基的封端基团,其中所述烷基的一个或多个碳任选地被杂原子取代;
y可以是选自1、2、3、4、5、6、7、8、9、10的整数;
T可以是具有两个或更多个官能团的部分,其中T和(L1)a之间的连接以及T和(L2)b之间的连接可以相同或不同;
L1和L2可以各自独立地是双官能团接头;
a和b各自可以是选自0、1、2、3、4、5、6、7、8、9、10的整数;
B可以是带支链的接头,其中每个支链可以包含延伸间隔物、触发单元、自消解间隔物或其任何组合,其中触发单元可以是可由酶(例如组织蛋白酶B、纤溶酶、基质金属蛋白酶(MMP)、β-葡萄糖醛酸酶、β-半乳糖苷酶)裂解的氨基酸序列或β-葡萄糖苷酸(β-glucoronide)或β-半乳糖苷触发部分;可以在酸性pH条件下释放药物D或其衍生物的pH敏感接头;或可通过谷胱甘肽、硫氧还蛋白家族成员(WCGH/PCK)或硫还原酶释放药物D或其衍生物的二硫键接头。
A可以是任何单特异性或多特异性抗体或抗原结合蛋白,包括抗体片段、单链抗体、纳米抗体或任何抗原结合片段,其针对抗原是一价或多价的;
D可以是任何细胞毒性小分子或肽或其衍生物,并且可以通过酶促裂解和/或自消解机制或者pH诱导的水解从B释放;每个D可以相同或不同;
n可以是选自1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24和25的整数。
在一些实施方案中,B的每个支链包含触发部分,例如氨基酸序列或二硫化物部分或β-葡萄糖苷或β-半乳糖胺,其通过自消解间隔物连接到药物D或直接连接到药物D。自消解间隔物的实例包括但不限于以下:
其中R1、R2、R3、R4可以是H或C1-10烷基。在这样的实施方案中,D可以是含有活性O或N或S官能团的任何小分子或肽药物或其衍生物。
在一些实施方案中,B的每个分支可以包含pH敏感接头,该接头可以在肿瘤部位和/或肿瘤细胞内部的酸性pH条件下释放药物D或其衍生物。酸性敏感接头的实例包括但不限于以下形式:
-CR1=N-NR1-、-CR1=N-O-、-CR1=N-NR2-CO-、-N=N-CO-、-OCOO-、-NR1-COO-。
在一些实施方案中,B的每个支链可以包含二硫键接头,该接头可以通过酶促裂解,例如通过谷胱甘肽、硫氧还蛋白家族成员(WCGH/PCK)或硫还原酶的酶促裂解,在肿瘤部位和/或肿瘤细胞内部释放药物D或其衍生物。
在一些实施方案中,A是单链双特异性抗体,其能够与两个Her2抗原上的两个不同的表位结合(SCAHer2IIxSCAHer2IV)。
在一些实施方案中,SCAHer2IIxSCAHer2IV的氨基酸序列可以是:
在一些实施方案中,A是单链抗Her2 x抗Her2单特异性抗体,其能够与两个Her2抗原上的两个相同的表位结合。
在一些实施方案中,SCAHer2IV/SCAHer2IV的氨基酸序列可以是:
在一些实施方案中,A是单链双特异性抗体,其能够与两种不同的抗原Her2和Her3结合(SCAHer2xSCAHer3)。
在一些实施方案中,SCAHer2IVxSCAHer3的氨基酸序列可以是:
在一些实施方案中,A是单链双特异性抗体,其与Met1和Met2结合(SCAc-Met1xSCAc-Met2)。
在一些实施方案中,SCAc-Met1xSCAc-Met2的氨基酸序列可以是:
在一些实施方案中,D可以通过酶促和/或自消解机制或pH诱导的水解在肿瘤部位或肿瘤细胞内部释放。
在一些实施方案中,D可以选自任何DNA交联剂、微管抑制剂、DNA烷化剂、拓扑异构酶抑制剂或其组合。
在一些实施方案中,D可以选自奥瑞他汀(MMAE,MMAF)、长春花生物碱、laulimalide、紫杉烷、秋水仙碱、美登素(DM1,DM4)、微管溶素(tubulysin)、念珠藻素(Cryptophycin)、哈米特林(Hemiasterlin)、西马多丁(Cemadotin)、根霉素(Rhizoxin)、圆皮海绵内酯(Discodermolide)、根薯酮内酯(taccalonolide)A或B或AF或AJ、根薯酮内酯AI-环氧化物、CA-4、埃博霉素A和B、laulimalide、紫杉醇、多西他赛、吡咯并苯二氮卓类、倍癌霉素、阿霉素、刺孢霉素、喜树碱、SN38、iSGD-1882、centanamycin、PNU-159682、uncialamycin、吲哚并苯二氮卓二聚体、β-鹅膏蕈碱、毒伞毒素(Amatoxin)、泰兰斯他汀类(thailanstatin)或其衍生物或类似物,或其组合。
在一些实施方案中,D是单甲基奥瑞他汀E(MMAE,一种抗有丝分裂药物)或其衍生物;或SN38(一种强效拓扑异构酶I抑制剂)或其衍生物;或其组合。
在另一个实施方案中,D与如4-氨基苄醇(PAB)的自消解间隔物以及如缬氨酸-瓜氨酸的触发部分连接以形成Val-Cit-PAB-D。
在本发明的一个方面,提供了制备聚乙二醇化药物缀合物的方法,该聚乙二醇化药物缀合物能够与蛋白质或抗体位点特异性缀合,所述抗体包括抗体片段或者单链单特异性或多特异性抗体。在本发明的另一个方面,提供了制备聚乙二醇化单链BsADC的方法。
为了合成聚乙二醇化的单链BsADC,可以合成1至5价单特异性单链抗体或单链双特异性抗体的编码序列或携带该编码序列的载体,并将其导入例如CHO表达系统。可以如先前所述(WO2018075308)表达和纯化蛋白质。
为了合成具有含位点特异性缀合官能团的侧链的聚乙二醇化药物缀合物,可以将聚乙二醇的末端官能团如羟基或羧基等活化并与三官能小分子部分例如Boc或Fmoc保护的赖氨酸缀合,以形成末端分支的异型双官能聚乙二醇。新形成的羧基可以与分支间隔物偶联以形成PEG-Lys(Boc)-B。偶联后,可以去除保护基团,未受保护的聚乙二醇化带支链接头可以与具有位点特异性缀合官能团如马来酰亚胺或DBCO的小分子接头偶联,以形成PEG-Lys(Mal)-B或PEG-Lys(DBCO)-B。诸如PEG-lys(Mal)-B-(Val-Cit-PAB-MMAE)n或PEG-lys(DBCO)-B-(Val-Cit-PAB-MMAE)n的聚乙二醇化药物缀合物,可以通过PEG-Lys(Mal)-B或PEG-Lys(DBCO)-B与Val-Cit-PAB-MMAE的偶联反应制备,其中n是例如2的整数。合成的最后一步是将聚乙二醇化药物缀合物与硫醇或叠氮化物标记的单链双特异性抗体进行位点特异性缀合。
可选地,为了合成具有含位点特异性缀合官能团的侧链的聚乙二醇化药物缀合物,可以在去除保护基团后,将聚乙二醇的末端官能团如羟基或羧基等活化并与三官能小分子部分,例如Boc或Fmoc保护的赖氨酸缀合,以形成末端分支的异型双官能聚乙二醇。脱保护后的聚乙二醇化合物可以与具有位点特异性缀合官能团的小分子接头如马来酰亚胺或DBCO偶联,以形成PEG-Lys(Mal)-OH或PEG-Lys(DBCO)-OH。PEG-Lys(Mal)-OH或PEG-Lys(DBCO)-OH随后可以与分支部分偶联,其中每个分支通过延伸间隔物、触发单元和/或自消解间隔物与药物D连接,以形成聚乙二醇化药物缀合物,例如PEG-lys(Mal)-B-(Val-Cit-PAB-MMAE)n或者PEG-lys(DBCO)-B-(Val-Cit-PAB-MMAE)n,其中n是例如2的整数。合成的最后一步是聚乙二醇化药物缀合物与硫醇或叠氮化物标记的单链双特异性抗体位点特异性缀合,以形成式Ia和Ib的化合物。可选地,可以使用类似的方法从可商购获得的异双官能聚乙二醇合成聚乙二醇化药物缀合物,从而形成式Ic的化合物。
II.聚乙二醇接头
在本发明的一个实施方案中,聚乙二醇可以是式:
在该式中,n可以是1至约2300的整数,以优选提供总分子量为5000至40000或更大的(如有需要)聚合物。M可以是H、甲基或其他低分子量烷基。M的非限制性实例包括H、甲基、乙基、异丙基、丙基、丁基或F1(CH2)qCH2。F和F1可以独立地是末端官能团,例如羟基、羧基、硫醇、卤化物、氨基等,其能够被官能团化、活化和/或与小分子间隔物或接头缀合。q和m可以是0至10的任何整数。
在本发明的另一个实施方案中,该方法也可以用另一种替代的带支链聚乙二醇进行。带支链聚乙二醇可以是式:
在该式中,PEG是聚乙二醇。m可以是2至10的整数,以优选提供总分子量为5000至80000或更大的(如有需要)带支链聚乙二醇。M可以是甲基或其他低分子量烷基。L可以是连接两个或多个聚乙二醇的功能性连接部分。这种连接部分的非限制性实例是:任何氨基酸,如甘氨酸、丙氨酸、赖氨酸,或1,3-二氨基-2-丙醇,三乙醇胺,连接有两个以上官能团的任何5元或6元芳环或脂族环。S是任何不可裂解的间隔物。F可以是末端官能团,如羟基、羧基、硫醇、氨基。i是0或1。当i等于0时,式如下所示:
其中:PEG、m、M或L的各变量的定义与上述相同。
本发明的方法也可以用替代的聚合物进行,如右旋糖酐、碳水化合物聚合物、聚环氧烷、聚乙烯醇或其他类似的非免疫原性聚合物,其末端基团能够被官能团化或活化。上述清单只是说明性的,并非意在限制适合在此使用的非抗原性聚合物的类型。
III.三官能接头T
T代表三官能接头,其与P、(L1)a和(L2)b连接。T可以衍生自具有三个官能团的任何组合的分子,所述官能团的非限制性实例包括羟基、氨基、肼基、叠氮化物、烯烃、炔烃、羧基(醛、酮、酯、羧酸、酸酐、酰基卤化物)、硫醇、二硫化物、腈、环氧化物、亚胺、硝基和卤化物。三官能接头中的官能团可以相同或不同。在一些实施方案中,可以对官能团中的一个或两个进行保护以实现与其他反应配体的选择性缀合。各种保护基团在本领域是已知的,包括例如March编著的《高级有机化学》(第三版,1985,Wiley and Sons,纽约)中显示的保护基团。在T和另一种反应配体反应之前或之后,还可以将官能团转化为其他基团。例如,羟基可以转化为甲磺酸(酯)或甲苯磺酸(酯)基团。卤化物可以用叠氮基代替。T的酸性官能团可以通过与含有末端炔烃的氨基偶联而转化为炔烃官能团。
在示例性实施方案中,T衍生自赖氨酸、1,3-二氨基-2-丙醇或三乙醇胺。这些分子上的一个或多个官能团可以被保护用于选择性反应。在一些实施方案中,T衍生自受Boc保护的赖氨酸。
IV.双官能接头L1和L2
接头L1和L2都包含可独立地选自(CH2)aXY(CH2)b-,-X(CH2)aO(CH2CH2O)c(CH2)bY-,-(CH2)a杂环基-,-(CH2)aX-和-X(CH2)aY-的接头链,其中a,b和c各自是选自0至25的整数,包括所有子单元;X或Y独立地选自C(=O)、NR1、S、O、CR2R3或无;R1,R2和R3代表氢、C1-10烷基或(CH2)1-10C(=O)。
接头L1和L2内的杂环基连接基团(无论其处于内部位置还是处于末端位置)可以衍生自基于马来酰亚胺基的部分。合适的前体的非限制性实例包括N-琥珀酰亚胺4-(马来酰亚胺甲基)环己烷甲酸酯(SMCC)、N-琥珀酰亚胺-4-(N-马来酰亚胺甲基)-环己烷-1-羧基-(6-脒基己酸酯)(LC-SMCC)、κ-马来酰亚胺十一酸N-琥珀酰亚胺酯(KMUA)、γ-马来酰亚胺丁酸N-琥珀酰亚胺酯(GMBS)、ε-马来酰亚胺己酸N-羟基琥珀酰亚胺酯(EMCS)、m-马来酰亚胺苯甲酰基-N-羟基琥珀酰亚胺酯(MBS)、N-(α-马来酰亚胺乙酰氧基)-琥珀酰亚胺酯(AMAS)、琥珀酰亚胺-6-(β-马来酰亚胺丙酰胺)己酸酯(SMPH)、N-琥珀酰亚胺4-(对马来酰亚胺苯基)-丁酸酯(SMPB)和N-(对马来酰亚胺苯基)异氰酸酯(PMPI)。
在一些其他非限制性示例性实施方案中,每个接头单元也可以衍生自基于卤代乙酰基的部分,其选自N-琥珀酰亚胺-4-(碘乙酰基)-氨基苯甲酸酯(SIAB)、N-琥珀酰亚胺碘乙酸酯(SIA)、N-琥珀酰亚胺溴乙酸酯(SBA)或N-琥珀酰亚胺基3-(溴乙酰氨基)丙酸酯(SBAP)。
可选地,接头的杂环基连接基团可以是四唑基或三唑基,其由不同的接头部分如DBCO和叠氮化物缀合形成。因此,杂环基团作为连接点。
在一些实施方案中,(L1)a和(L2)b各自可以包含:
-X1-(CH2)aC(O)NR(CH2)bO(CH2CH2O)c(CH2)dC(O)-或
-C(O)(CH2)aO(CH2CH2O)b(CH2)cX2C(O)(CH2)dNR-或
-X3-(CH2)aC(O)NR(CH2)bO(CH2CH2Q)c(CH2)dX2C(O)(CH2)eC(O)-,
其中X1、X2和X3可以相同或不同,并且独立地表示杂环基;
a,b,c,d和e各自是选自0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25的整数;并且
R代表氢或C1-10烷基。
在一些实施方案中,X1和/或X3衍生自基于马来酰亚胺基的部分。在一些实施方案中,X2代表含有三唑基或四唑基的基团。在一些实施方案中,R代表氢。在一些实施方案中,a,b,c,d和e各自独立地选自0、1、2、3、4、5、6、7、8、9和10。
在一些示例性实施方案中,(L1)a和(L2)b可以选自:
其中n和m是整数并且独立地选自0至20。
V.带支链接头B
带支链接头B可包含分支单元、延伸间隔物、触发单元、自消解间隔物或其任何组合。
在一些实施方案中,分支单元包含可以独立地选自以下的结构:
X,Y,Z,W=C(O)、NR1、NR2、O、N或无
a,b,c=0至10
R1和R2独立地代表氢或C1-10烷基基团。
在其他实施方案中,分支单元包括可以独立地选自以下的结构:
X,Y,Z,U,V,W=C(O)、NR1、NR2、O、N或无
a,b,c,d,e=0至10
R1和R2独立地代表氢原子或C1-10烷基基团。
在一些实施方案中,每个分支中的延伸间隔物包含接头链,该接头链可以独立地选自:
-X(CH2)aO(CH2CH2O)b(CH2)cY-,-X(CH2)aY-,
或其任何组合,其中a,b和c各自是选自0至25的整数,包括所有子单元;X和Y可以独立地选自NR1、NR2、C(O)、O或无;R1和R2独立地代表氢或C1-10烷基。
在其他实施方案中,触发单元包括任何氨基酸序列或任何碳水化合物部分或二硫化物或任何可通过酶促或化学方法裂解的可裂解键。
在一些实施方案中,自消解间隔物包含可以选自以下的结构:
其中R1,R2,R3和R4独立地表示氢或C1-10烷基;X和Y可以是NH或O或S,c选自1或2。
在一些实施方案中,自消解间隔物是
在一些实施方案中,带支链接头B可以选自:
其中:
a,b,c,d,e和f各自为选自1至25的整数;
(A)n为氨基酸序列触发单位,每个A为独立的氨基酸,n为1至25的任意整数;
PAB是对氨基苄醇;
Ex是包含接头链的延伸间隔物,可以独立地选自:
-NR1(CH2)aO(CH2CH2O)b(CH2)cC(O)-,
-C(O)(CH2)aNR1-,
-NR1(CH2)aO(CH2CH2O)b(CH2)cNR2-,NR1(CH2)xO(CH2CH2O)y(CH2)zNR2-,
-NR1(CH2)aNR2-,-NR1(CH2)xNR2-,
-NR1(CH2)aO(CH2CH2O)b(CH2)cO-,-NR1(CH2)aO(CH2CH2O)b(CH2)cC(O)-,
-O(CH2)aNR1-,
-C(O)(CH2)aO-,
-O(CH2)aO(CH2CH2O)b(CH2)cC(O)--NR1(CH2)aO(CH2CH2O)b(CH2)cC(O)-,
-C(O)(CH2)aO(CH2CH2O)b(CH2)cC(O)-,-NR1(CH2)aO(CH2CH2O)b(CH2)cC(O)-,
-C(O)(CH2)aC(O)-,
或无;
其中a,b和c各自是选自0至25的整数,包括所有子单元;R1和R2独立地代表氢或C1-10烷基。
在另一些实施方案中,氨基酸序列触发单元可以是Val-Cit、al-Ala、Val-Lys、Phe-Lys、Phe-Cit、Phe-Arg、Phe-Ala、Ala-Lys、Leu-Cit、Ile-Cit、Trp-Cit、D-Phe-LPhe-Lys、Phe-Phe-Lys、D-Phe-Phe-Lys、Gly-Phe-Lys、Gly-Phe-Leu-Gly、或Ala-Leu-Ala-Leu;或者它们的受保护形式。
对于优选的实施方案,氨基酸序列可以是Val-Cit、Phe-Lys或Val-Lys。
在一些示例性实施方案中,带支链接头B可以选自:
VI.连接基团
本发明的缀合物的不同部分可以通过各种化学连接进行连接。实例包括但不限于酰胺、酯、二硫键、醚、氨基、氨基甲酸酯、肼、硫醚和碳酸酯。例如,可以活化聚乙二醇部分(P)的末端羟基,然后与赖氨酸(T)偶联,以在式Ia或Ib的P和T之间提供所需的连接点。T和L1之间或T和L2之间或L2和B之间的连接基团可以是酰胺,其由接头L2的氨基与赖氨酸(T)的羧基之间或L1的羧基与T的氨基之间或L2的羧基与B的氨基之间的反应产生。根据缀合物的预期特性,也可以在抗体部分(A)与相邻的接头L1之间或任何两个氨基酸之间或氨基酸与对氨基苄醇之间引入合适的连接基团。
在一些实施方案中,缀合物的不同部分之间的连接基团可以衍生自彼此具有固有的化学亲和力或选择性的一对官能团的偶联。这些类型的偶联或成环允许位点特异性缀合,以引入蛋白质或抗体部分的。导致位点特异性缀合的官能团的非限制性实例包括硫醇、马来酰亚胺、2’-吡啶基二硫代变体、芳族砜或乙烯基砜、丙烯酸酯、溴代或碘代乙酰胺、叠氮化物、炔烃、二苯并环辛基(DBCO)、羰基、2-氨基-苯甲醛或2-氨基-苯乙酮基团、酰肼、肟、酰基三氟硼酸钾、O-氨基甲酰基羟基胺、反式环辛烯、四嗪、三芳基膦、硼酸、炔烃。
VII.细胞毒性化合物D
在一些实施方案中,D可以包括但不限于美登素(DM1,DM4)(US 5208020;US5416064;EP 0425235)、奥瑞他汀衍生物,例如单甲基奥瑞他汀E(MMAE)和F(MMAF)(US5635483;US 5780588;US 7498298)、吡咯并苯二氮卓类、西马多丁、SN38、圆皮海绵内酯、根薯酮内酯A或B或AF或AJ、根薯酮内酯AI-环氧化物、CA-4、长春花生物碱、iSGD-1882、吲哚并苯二氮卓二聚体、uncialamycin、centanamycin、laulimalide、尾海兔素(dolastatin)、泰兰斯他汀类、毒伞毒素、β鹅膏蕈碱、哈米特林、倍癌霉素、PNU-159682、秋水仙素、微管溶素、刺孢霉素或其衍生物(US 5712374;US 5714586;US 5739116;US 5767285;US 5770701;US5770710;US 5773001;US 5877296;Hinman,L.M.等人,Cancer Res.,1993,53,3336-3342;Lode,H.N.等人,Cancer Res.,1998,58,2925-2928)、蒽环类,如道诺霉素或阿霉素(Kratz,F等人,Curr.Med.Chem.,2006,13,477-523;Jeffrey,S.C.等人,Bioorg.Med.Chem.Lett.,2006,16,358-362;Torgov,M.Y.等人,Bioconjug.Chem.,2005,16 717-721;Nagy,A.等人,Proc.Natl.Acad.Sci.USA,2000,97,829-834;Dubowchik,G.M.等人,Bioorg.Med.Chem.Lett.,2002,12,1529-1532;King,H.D.等人,J.Med.Chem.,2002,45,4336-4343;US 6630579)、甲氨蝶呤、长春地辛、紫杉烷类如多西他赛、紫杉醇、拉罗紫杉醇(larotaxel)、泰司紫杉醇(tesetaxel)和奥他紫杉醇(ortataxel)、单端孢霉烯(trichothecene)和CC-1065。
在其他实施方案中,D可以是酶促活性毒素或其片段,包括但不限于白喉A链、白喉毒素的非结合活性片段、外毒素A链(来自铜绿假单胞菌(Pseudomonas aeruginosa))、蓖麻毒蛋白A链、相思豆毒素A链、莫德霉素(modeccin)A链、α-sarcin、油桐(aleurites fordii)蛋白、石竹素(dianthin)蛋白、美洲商陆蛋白(phytolaca americana)(PAPI、PAPII和PAP-S)、苦瓜抑制剂、麻疯树毒素(curcin)、巴豆素、皂草抑制剂、白树毒素(gelonin)、mitogellin、局限曲菌素(restrictocin)、酚霉素(phenomycin)和伊诺霉素。
在其他一些实施方案中,D可以是放射性原子。各种放射性同位素可用于产生放射性缀合物。例如At211、I131、I125、Y90、Re186、Re188、Sm153、Bi212、P32、Pb212、和Lu的放射性同位素。当放射性缀合物用于检测时,其可以包括用于闪烁法(scintigraphic)研究的放射性原子,例如Tc99或I123,或用于磁共振成像(MRI)的自旋标记物,例如I123、I131、In111、F19、C13、N15、O17、钆、锰或铁。
在更多的实施方案中,D可以包括烷化剂,例如噻替哌和环磷酰胺;烷基磺酸盐,如白消安、丙硫丹和哌硫丹;氮丙啶类如苯并多巴、碳醌、美托多巴、乌多巴;乙烯亚胺和甲基三聚氰胺,包括三乙胺、三亚乙基三聚氰胺、三亚乙基磷酰胺、三亚乙基硫代磷酰胺和三羟甲基三聚氰胺;醋酸菌素(尤其是布拉他辛和布拉他西酮);喜树碱(包括合成类似物拓扑替康);苔藓抑素;卡司他丁;CC-1065(包括其合成类似物,阿多来新、卡泽来新和比泽来新);念珠藻素(特别是念珠藻素1和念珠藻素8);尾海兔素;倍癌霉素(包括合成类似物KW-2189和CBI-TMI);五加素;潘克拉他汀;嗜血素;海绵抑素;氮芥类,如苯丁酸氮芥、氯萘嗪、胆磷酰胺、雌莫司汀、异环磷酰胺、甲氯乙胺、盐酸甲氯乙胺、美法仑、诺夫比钦、苯乙炔、泼尼莫司汀、曲磷酰胺、尿嘧啶芥;硝基脲类,如卡莫司汀、氯唑菌素、福替莫司汀、洛莫司汀、尼莫司汀、雷尼莫司汀;抗生素,例如烯二炔抗生素,例如刺孢霉素(Nicolaou,K.C.等人,AgnewChem.Intl.Ed.,1994,33,183-186)、动力霉素、埃斯帕霉素以及新制癌素发色团和相关的色蛋白烯二炔抗生素发色团、阿克拉霉素、放线菌素、红霉素、氮杂丝氨酸、博来霉素、仙人掌霉素、角霉素、樟脑霉素、亲碳素、色霉素、更生霉素、柔红霉素、地托霉素、6L-正亮氨酸、阿霉素(包括吗啉代多柔比星、氰基吗啉代多柔比星、2-吡咯啉-多柔比星和脱氧多柔比星)、表柔比星、依柔比星、伊达比星、马塞洛霉素、丝裂霉素、霉酚酸、诺加霉素、橄榄霉素、培普霉素、苯丙霉素、嘌呤霉素、奎拉霉素、罗柔比星、链霉素、链脲佐菌素、结核菌素、乌苯美司、吉诺他汀、唑柔比星;抗代谢物,如甲氨蝶呤和5-氟尿嘧啶(5-FU);叶酸类似物,如地蝶呤、蝶蝶呤、曲美沙酯;嘌呤类似物,例如氟达拉滨、6-巯基嘌呤、硫胺嘌呤、硫鸟嘌呤;嘧啶类似物,例如阿西他滨、阿扎胞苷、6-氮杂尿苷、卡莫氟、阿糖胞苷、双脱氧尿苷、多西氟尿苷、依西他滨、氟尿苷、5-FU;雄激素,例如卡甾酮、丙酸卓莫他酮、表甾烷醇、美皮司坦、睾酮内酯;抗肾上腺素,如氨鲁米特、米托坦、曲洛司坦;叶酸补充剂,如弗林酸;乙酰丙酮;醛磷酰胺糖苷;氨基乙酰丙酸;安吖啶;贝司他韦;比生群;依达沙酯;去脂胺;地美可辛;二嗪酮;乙二胺;依利醋铵;埃博霉素;乙醇酸;硝酸镓;羟基脲;香菇多糖;氯硝胺;美登素类,如美登素和安丝菌素;米托瓜松;米托蒽醌;莫匹达莫;硝酸腺苷;喷司他丁;蛋氨氮芥;吡柔比星;鬼臼酸;2-乙基酰肼;丙卡巴肼;雷佐生;根瘤菌素;四唑呋喃;螺锗;牛磺酸;三嗪酮;2,2′,2″-三氯三乙胺;单端孢霉烯(尤其是T-2毒素、藜芦素A、胭脂虫红素A和胍丁胺);氨基甲酸酯;长春花;达卡巴嗪;甘露醇;二溴甘露醇;二溴卫矛醇;匹布罗曼;加胞嘧啶;阿拉伯糖苷;环磷酰胺;噻替哌;紫杉烷类,例如紫杉醇和多西他赛苯丁酸氮芥;吉西他滨;6-硫鸟嘌呤;巯嘌呤;铂类似物,如顺铂和卡铂;长春碱;铂;依托泊苷(VP-16);异环磷酰胺;丝裂霉素C;米托蒽醌;长春新碱;长春瑞滨;诺维本;诺凡酮;替尼泊苷;道诺霉素;氨基蝶呤;希罗达;伊班膦酸盐;CPT-11;拓扑异构酶抑制剂鲁比替康(9-硝基喜树碱或RFS-2000);二氟甲基鸟氨酸;视黄酸;卡培他滨;以及任何上述物质的药学上可接受的盐、酸或衍生物。该定义中还包括用于调节或抑制激素对肿瘤的作用的抗激素剂,例如抗雌激素剂,包括例如他莫昔芬、雷洛昔芬、4-羟基他莫昔芬、三苯氧胺、酮昔芬、LY117018、奥那普司酮和托瑞米芬;抗雄激素剂,例如氟他胺、尼鲁他胺、比卡鲁胺、亮丙瑞林、戈舍瑞林;以及任何上述物质的药学上可接受的盐、酸或衍生物。
VIII.抗体和靶标
目前已知有许多针对细胞表面分子和/或其配体的治疗性抗体。这些抗体可用于选择和构建单特异性或多特异性ADC中的特制特异性识别结合部分。例如博纳吐单抗/BLINCYTO(CD3/CD19)、Rituxan/MabTHera/利妥昔单抗(CD20)、H7/奥瑞珠单抗(CD20)、Zevalin/Ibrizumomab(CD20)、Arzerra/奥伐木单抗(CD20)、HLL2/依帕珠单抗、Inotuzomab(CD22)、Zenapax/达克珠单抗、Simulect/巴利昔单抗(CD25)、赫赛汀/曲妥单抗、帕妥珠单抗(Her2/ERBB2)、Mylotarg/吉妥珠单抗(CD33)、Raptiva/依法珠单抗(Cd11a)、Erbitux/西妥昔单抗(EGFR,表皮生长因子受体)、IMC-1121B(VEGF受体2)、Tysabri/那他珠单抗(a4β1和α4β7整联蛋白的α4-亚单位)、ReoPro/阿昔单抗(gpIIb-gpIIa和αvβ3-整联蛋白)、Orthoclone OKT3/Muromonab-CD3(CD3)、Benlysta/贝利木单抗(BAFF)、Tolerx/Oteliximab(CD3)、Soliris/依库丽单抗(C5补体蛋白)、Actemra/托珠单抗(IL-6R)、Panorex/依决洛单抗(EpCAM,上皮细胞粘附分子)、CEA-CAM5/Labetuzumab(CD66/CEA,癌胚抗原)、CT-11(PD-1,程序性死亡-1T-细胞抑制受体,CD-d279)、H224G11(c-Met受体)、SAR3419(CD19)、IMC-A12/Cixutumumab(IGF-1R、胰岛素样生长因子1受体)、MEDI-575(PDGF-R、血小板-衍生的生长因子受体)、CP-675、206/曲美目单抗(细胞毒性T淋巴细胞抗原4)、RO5323441(胎盘生长因子或PGF)、HGS1012/马帕木单抗(TRAIL-R1)、SGN-70(CD70)、Vedotin(SGN-35)/本妥昔单抗(CD30)和ARH460-16-2(CD44)。
本发明公开的单特异性或多特异性ADC可用于药物的制备,所述药物用于治疗肿瘤疾病、心血管疾病、感染性疾病、炎性疾病、自身免疫性疾病、代谢(例如内分泌)疾病、或神经系统(例如神经变性)疾病。这些疾病的示例性非限制性实例为阿尔茨海默病、非霍奇金淋巴瘤、B-细胞急性和慢性淋巴性白血病、伯基特淋巴瘤、霍奇金淋巴瘤、毛细胞性白血病、急性和慢性骨髓性白血病、T-细胞淋巴瘤和白血病、多发性骨髓瘤、神经胶质瘤、Waldenstrom巨球蛋白血症、癌(如口腔、胃肠道、结肠、胃、肺道、肺、乳腺、卵巢、前列腺、子宫、子宫内膜、宫颈、膀胱、胰腺、骨、肝、胆囊、肾、皮肤、和睾丸的癌)、黑素瘤、肉瘤、神经胶质瘤和皮肤癌、急性特发性血小板减少性紫癜、慢性特发性血小板减少性紫癜、皮肌炎、西登哈姆氏舞蹈病、重症肌无力、系统性红斑狼疮、狼疮性肾炎、风湿热、多腺体综合征、大疱性类天疱疮、糖尿病、Henoch-Schonlein紫癜、链球菌感染后肾炎、结节性红斑、Takayasu动脉炎、Addison疾病、类风湿性关节炎、多发性硬化、肉样瘤病、溃疡性结肠炎、多形性红斑、IgA肾病、结节性多动脉炎、强直性脊柱炎、Goodpasture综合征、闭塞性血栓性脉管炎、Sjogren综合征、原发性胆汁性肝硬化、Hashimoto甲状腺炎、甲状腺毒症、硬皮病、慢性活动性肝炎、多发性肌炎/皮肌炎、多软骨炎、寻常天疱疮、Wegener肉芽肿病、膜性肾病、肌萎缩侧索硬化、脊髓痨、巨细胞动脉炎/多肌痛、恶性贫血、快速进行性肾小球性肾炎、牛皮癣、或纤维化肺泡炎。
目前已知许多细胞表面标记物及其配体。例如,已报道癌细胞表达至少一种下列细胞表面标志物和/或配体,包括但不限于,碳酸酐酶IX、α-甲胎蛋白、α-辅肌动蛋白-4、A3(对A33抗体特异的抗原)、ART-4、B7、Ba-733、BAGE、BrE3-抗原、CA125、CAMEL、CAP-1、CASP-8/m、CCCL19、CCCL21、CD1、CD1a、CD2、CD3、CD4、CDS、CD8、CD1-1A、CD14、CD15、CD16、CD18、CD19、CD20、CD21、CD22、CD23、CD25、CD29、CD30、CD32b、CD33、CD37、CD38、CD40、CD40L、CD45、CD46、CD54、CD55、CD59、CD64、CD66a-e、CD67、CD70、CD74、CD79a、CD80、CD83、CD95、CD126、CD133、CD138、CD147、CD154、CDC27、CDK-4/m、CDKN2A、CXCR4、CXCR7、CXCL12、HIF-1-α、结肠特异性抗原-p(CSAp)、CEA(CEACAM5)、CEACAM6、c-met、DAM、EGFR、EGFRvIII、EGP-1、EGP-2、ELF2-M、Ep-CAM、Flt-1、Flt-3、叶酸受体、G250抗原、GAGE、GROB、HLA-DR、HM1.24、人绒毛膜促性腺激素(HCG)及其亚基、Her2/neu、HMGB-1、缺氧诱导因子(HIF-1)、HSP70-2M、HST-2或1a、IGF-1R、IFN-γ、IFN-α、IFN-β、IL-2、IL-4R、IL-6R、IL-13R、IL-15R、IL-17R、IL-18R、IL-6、IL-8、IL-12、IL-15、IL-17、IL-18、IL-25、胰岛素样生长因子-1(IGF-1)、KC4-抗原、KS-1-抗原、KS 1-4、LAG3、Le-Y、LDR/FUT、巨噬细胞迁移抑制因子(MIF)、MAGE、MAGE-3、MART-1、MART-2、NY-ESO-1、TRAG-3、mCRP、MCP-1、MIP-1A、MIP-1B、MIF、MUC1、MUC2、MUC3、MUC4、MUC5、MUM-1/2、MUM-3、NCA66、NCA95、NCA90、胰腺癌粘蛋白、胎盘生长因子、p53、PLAGL2、前列腺酸磷酸酶、PSA、PRAME、PSMA、P1GF、ILGF、ILGF-1R、IL-6、IL-25、RS5、RANTES、T101、SAGE、5100、存活蛋白、存活蛋白-2B、TAC、TAG-72、生腱蛋白、TRAIL受体、TNF-α、Tn-抗原、Thomson-Friedenreich抗原、肿瘤坏死抗原、VEGFR、ED-B纤连蛋白、WT-1、17-1A-抗原、补体因子C3、C3a、C3b、C5a、C5、血管发生标志物、bcl-2、bcl-6、Kras、c-MET、致癌基因标志物和致癌基因产物(Sensi,M.等人,Clin.Cancer Res.,2006,12,5023-5032;Parmiani,G.等人,J.Immunol.,2007,178,1975-1979;Castelli,C.等人,Cancer Immunol.ImmunotHer.,2005,54,187-207)。因此,识别这种特异性细胞表面受体或其配体的抗体可用于本发明的单特异性或多特异性ADC中的特异性和选择性识别结合部分,从而靶向并结合疾病相关的多种细胞表面标志物或配体。
在一些实施方案中,为了治疗癌症/肿瘤,单特异性或多特异性ADC用于靶向肿瘤相关抗原(TAA),例如在Herberman的“癌症免疫诊断”,在FleisHer编辑的“癌症临床生物化学”,347页(American Association of Clinical Chemists,1979)以及US 4150149;US4361544;US4444744中报道的那些。
关于肿瘤相关抗原的报道包括Mizukami等人,Nature Med.2005 11,992-997;Hatfield等人,Curr.Cancer Drug Targets 2005,5229-248;Vallbohmer等人,J.Clin.Oncol.2005,23,3536-3544;以及Ren等人,Ann.Surg.2005,242,55-63,关于鉴别的肿瘤相关抗原,每篇通过引用并入本发明。当疾病涉及淋巴瘤、白血病或自身免疫病时,靶向抗原可选自CD4、CD5、CD8、CD14、CD15、CD19、CD20、CD21、CD22、CD23、CD25、CD33、CD37、CD38、CD40、CD40L、CD46、CD54、CD67、CD74、CD79a、CD80、CD126、CD138、CD154、CXCR4、B7、MUC1或1a、HM1.24、HLA-DR、生腱蛋白、VEGF、P1GF、ED-B纤连蛋白、致癌基因、致癌基因产物(例如c-Met或PLAGL2)、CD66a-d、坏死抗原、IL-2、T101、TAG、IL-6、MIF、TRAID-R1(DR4)和TRAIL-R2(DR5)。
针对上述抗原的抗体可用作制备本发明的ADC或BsADC的结合结构域或部分。可以制备不同的BsADC针对两种不同的靶标。
抗原对的实例包括CD19/CD3、BCMA/CD3、Her家族的不同抗原组合(EGFR、HER2、HER3)、IL17RA/IL7R、IL-6/IL-23、IL-1-β/IL-8、IL-6或IL-6R/IL-21或IL-21R、ANG2/VEGF、VEGF/PDGFR-β、血管内皮生长因子-(VEGF)受体2/CD3、PSMA/CD3、EPCAM/CD3、选自VEGFR-1、VEGFR-2、VEGFR-3的抗原的组合、FLT3、c-FMS/CSF1R、RET、c-Met、EGFR、Her2/neu、HER3、HER4、IGFR、PDGFR、c-KIT、BCR、整联蛋白和具有水溶性配体的MMP,其选自VEGF、EGF、PIGF、PDGF、HGF、和血管生成素,ERBB-3/C-MET、ERBB-2/C-MET、EGF受体1/CD3、EGFR/HER3、PSCA/CD3、c-Met/CD3、内皮唾酸蛋白/CD3、EPCAM/CD3、IGF-1R/CD3、FAPALPHA/CD3、EGFR/IGF-1R、IL 17A/F、EGF受体1/CD3、和CD19/CD16。双特异性ADC的其他实例可具有(i)针对抗原的糖表位的第一特异性,所述抗原选自Lewis x-、Lewis b-和Lewis y结构、Globo H结构、KH1、Tn-抗原、TF-抗原和粘蛋白的碳水化合物结构、CD44、糖脂和鞘糖脂类、如Gg3、Gb3、GD3、GD2、Gb5、Gm1、Gm2、和唾液酸四糖神经酰胺,和(ii)针对ErbB受体酪氨酸激酶的第二特异性,所述ErbB受体酪氨酸激酶选自EGFR、HER2、HER3和HER4。与第二抗原结合位点组合的GD2与选自以下的免疫细胞相关:T-淋巴细胞、NK细胞、B-淋巴细胞、树突细胞、单核细胞、巨噬细胞、中性粒细胞、间充质干细胞、神经干细胞。
可以使用本发明公开的方法将单特异性或双特异性抗体与另一种单特异性或双特异性抗体连接在一起以制备多特异性ADC。通过使用已经可用的单特异性或双特异性治疗性结合实体,例如上述那些治疗性抗体,可以实现所需多特异性结合分子的快速且容易的产生。通过组合两种或更多种单一治疗分子以同时靶向和结合两个或更多个不同表位,从而定制产生多特异性ADC,可以预期与单一靶向ADC相比的加合/协同效应。
在一些实施方案中,使用抗体对制备本发明的多特异性ADC,该抗体对与如下靶标对特异性相互作用并显示出可测量的亲和力。
在一些实施方案中,BsADC包含双特异性单链抗体,其中所述双特异性单链抗体的两个结合域通过接头连接。在一些实施方案中,接头包含诸如半胱氨酸或非天然氨基酸残基的部分,其可用于抗体与非免疫原性聚合物药物缀合物如聚乙二醇化药物缀合物的位点特异性缀合。在一些其他实施方案中,双特异性单链抗体的两个结合域中的一个或两个包含半胱氨酸或非天然氨基酸残基,其可用于抗体与非免疫原性聚合物药物缀合物如聚乙二醇化药物缀合物的位点特异性缀合。
在一个优选的实施方案中,BsADC是两种抗体或其抗原结合片段(例如Fab,scFv等)的缀合物,其与Her2的两个不同表位特异性相互作用并显示出可测量的亲和力。
IX.合成
一旦选择了所需大小和分支数量的聚乙二醇,聚乙二醇的末端官能团,如羟基、羧基等,可以使用任何本领域公认的方法(WO2018075308)转化为末端分支的异型双官能团。广义地说,末端分支的异性双官能聚乙二醇可以通过如下方法制备:用N-羟基琥珀酰亚胺激活聚乙二醇的末端羟基或羧基,在如4-二甲氨基吡啶(DMAP)、吡啶等的碱的存在下,在聚乙二醇末端为羟基的情况下,使用如二(N-琥珀酰亚胺)碳酸酯(DSC)、三光气(triphosgene)等的试剂,或者在聚乙二醇末端为羧基的情况下,使用如N,N-二异丙基碳二亚胺(DIPC)、1-乙基-3-(3-二甲氨基丙基)碳二亚胺(EDC)等的偶联试剂,以形成活化的聚乙二醇。
接下来,在如二异丙胺(DIPEA)的碱的存在下,活化的聚乙二醇可以与三官能小分子如赖氨酸衍生物H-Lys(Boc)-OH反应,以形成具有游离羧基和受Boc保护的氨基的末端分支的异型双官能聚乙二醇PEG-Lys(Boc)-COOH。普通技术人员将理解,聚乙二醇的其他末端官能团如卤化物、氨基、硫醇基团等和其他三官能小分子可作为替代物用于相同目的(如果需要),所述三官能小分子包含来自-NH2、-NHNH2、-COOH、-OH、-C(O)X(X=卤化物)、-N=C=O、-SH、酸酐、卤化物、马来酰亚胺基、C=C、C≡C等或它们的受保护形式的列表的三个官能团的任意组合。
通过TFA除去Boc,然后与马来酰亚胺标记的间隔物如NHS-PEG2-马来酰亚胺反应,产生PEG-Lys(Mal)-COOH。
另外,与触发单元(例如val-cit)以及自消解间隔物(例如PABC)连接的细胞毒性药物(例如MMAE)通过偶联试剂如EDC/HOBT与分支单元偶联,以产生B-D:例如:
可以通过将PEG-Lys(MAL)-COOH与B-D通过偶联试剂如DCC偶联来形成靶标产物,即聚乙二醇化的药物缀合物PEG-Lys(Mal)-(Val-Cit-PAB-MMAE)2。
可以通过表达系统的遗传操作制备针对抗原为二价的单特异性抗体或如SCAHer2IIxSCAHer2IV的双特异性抗体。例如,可以合成编码双特异性scFv的DNA并将其引入表达系统(例如,CHO细胞)中。目的蛋白质随后表达并通过色谱技术纯化。
为了制备针对抗原为二价的聚乙二醇化单链ADC或BsADC,具有马来酰亚胺或DBCO官能团的聚乙二醇化药物缀合物可以与遗传插入或衍生的双功能抗体如SCAHer2IVxSCAHer2IV或SCAHer2IIxSCAHer2IV的游离硫醇或叠氮化物官能团进行位点特异性反应,以形成PEG-Lys(SCAHer2IVxSCAHer2IV)-(Val-Cit-PAB-MMAE)2或PEG-Lys(SCAHer2IIxSCAHer2IV)-(Val-Cit-PAB-MMAE)2。
可以使用多特异性抗体代替单特异性或双特异性抗体来类似地制备聚乙二醇化的多特异性抗体。
除了在本发明中列举的硫醇/马来酰亚胺或DBCO/叠氮化物位点特异性缀合基团对之外,普通技术人员将理解,其他已知的位点特异性缀合基团对,例如反式环辛烯/四嗪对;羰基/酰肼;羰基/肟;Suzuki-Miyaura交叉偶联试剂对;Sonogashira交叉偶联试剂对;Staudinger连接反应试剂对;Knoevenagel-Intra Michael加成试剂对;活性胺/丙烯酸酯对等可类似地设计并用作替代方案用于相同目的(如有需要)。上述位点特异性缀合基团对列表只是说明性的,并非意在限制适合在此使用的位点特异性缀合基团对的类型。
X.组合物
本发明还提供了组合物,例如,药物组合物,其包含与药学上可接受的载体共同配制的本发明的化合物。例如,本发明的药物组合物可包含与Her2受体的两种不同表位结合的化合物(例如双特异性抗体药物缀合物)。
本发明的治疗制剂可以通过将具有所需纯度的单特异性或多特异性分子药物缀合物与可选的生理学上可接受的载体、赋形剂或稳定剂混合来制备,后者可以是冻干制剂或水溶液形式。可接受的载体、赋形剂或稳定剂在所用剂量和浓度下对接受者无毒,且包括缓冲剂,如磷酸盐、柠檬酸盐和其他有机酸;抗氧化剂,包括抗坏血酸和蛋氨酸;防腐剂(如十八烷基二甲基苄基氯化铵;氯化六甲铵;苯扎氯铵;苄索氯铵;苯酚、丁醇或苄醇;对羟苯甲酸烷基酯如对羟苯甲酸甲酯或对羟苯甲酸丙酯;儿茶酚;间苯二酚;环己醇;3-戊醇;和间甲酚);低分子量(少于约10个残基)蛋白质,如血清白蛋白、明胶、或免疫球蛋白;亲水性聚合物如聚乙烯吡咯烷酮;氨基酸如甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸、或赖氨酸;单糖、二糖、和其它碳水化合物;螯合剂如EDTA;糖如蔗糖、甘露醇、海藻糖或山梨醇;成盐抗衡离子如钠;金属络合物(例如,Zn-蛋白质络合物);和/或非离子表面活性剂如TWEEN、普朗尼克、或聚乙二醇。
制剂还可根据所治疗的特定适应症的需要,包含一种以上的活性化合物,优选那些具有互补活性且不会相互产生不利影响的化合物。例如,制剂可以进一步包含另一种抗体或多特异性抗体、细胞毒剂、化学治疗剂或ADC。这些分子可以适当地以对预期目的有效的数量组合存在。
活性成分也可以被包裹在通过例如凝聚技术或界面聚合制备的微胶囊中,例如羟甲基纤维素或明胶微胶囊和聚(甲基丙烯酸甲酯)微胶囊,分别在胶体药物递送系统(例如脂质体、白蛋白微球、微乳液、纳米颗粒和纳米胶囊)或粗乳液中。此类技术公开于Remington′s Pharmaceutical Sciences第16版,Osol,A.Ed.(1980)。
可以制备缓释制剂。缓释制剂的合适实例包括含有单特异性或多特异性分子的固体疏水聚合物半透性基质,该基质呈成型制品的形式,例如薄膜或微胶囊。缓释基质的实例包括聚酯、水凝胶(例如,聚(2-羟乙基甲基丙烯酸酯)或聚(乙烯醇))、聚丙交酯(US3773919)、L-谷氨酸和γ-乙基-L-谷氨酸的共聚物、不可降解的乙烯-乙酸乙烯酯、可降解的乳酸-乙醇酸共聚物,如Lupron Depot(由乳酸-乙醇酸共聚物和乙酸亮丙瑞林组成的可注射微球)和聚-d(-)-3-羟基丁酸。诸如乙烯-醋酸乙烯酯和乳酸-乙醇酸之类的聚合物能够释放分子超过100天,某些水凝胶会在更短的时间内释放蛋白质。当包封的抗体在体内长时间滞留时,它们可能会因暴露在37℃下的湿气中而发生变性或聚集,从而导致生物活性丧失和免疫原性的可能变化。可以根据所涉及的机制设计合理的稳定策略。例如,如果发现聚集机制是通过硫代二硫化物交换形成分子间S-S键,则可以通过修饰巯基残基、从酸性溶液中冻干、控制水分含量、使用适当的添加剂和开发特定的聚合物基质组合物来实现稳定化。
本发明的药物组合物可以与疗法组合施用,即与其他药剂组合施用。下面更详细地描述可用于联合疗法的治疗剂的实例。
用于体内施用的制剂必须是无菌的。这可以通过无菌过滤膜过滤很容易地实现。无菌可注射溶液可以通过将所需量的活性化合物加入适当的溶剂中而制备,根据需要,与上述一种成分或多种成分组合,然后进行灭菌微滤。一般来说,制备分散液的方法是将活性化合物加入无菌载体中,该载体含有基本的分散介质和上面列举的其他所需成分。在制备无菌可注射溶液的无菌粉末的情况下,优选的制备方法是真空干燥和冷冻干燥(冻干),从先前无菌过滤的溶液产生活性成分加上其中的任何另外的期望成分的粉末。
XI.剂量
可与载体材料组合以产生单一剂型的活性成分的量将取决于被治疗的对象和特定的施用方式。可与载体材料组合以产生单一剂型的活性成分的量通常是产生治疗效果的组合物的量。通常,在100%中,该量的范围为约0.01%至约99%的活性成分,优选为约0.1%至约70%,最优选的为约1%至约30%的活性成分与药学上可接受的载体的组合。
调整剂量方案以提供最佳的预期反应(例如,治疗反应)。例如,可以单次施用,在一段时间内分几次施用,或者根据治疗情况的紧急程度按比例减少或增加剂量。以剂量单位形式配制肠胃外组合物以便于施用和剂量均匀是特别有利的。如本发明所用的剂量单位形式是指适合作为待治疗受试者的单位剂量的物理上离散的单元:每个单元含有预定量的活性化合物,经计算可与所需的药物载体一起产生所需的治疗效果。本发明的剂量单位形式的规格由以下决定并且直接取决于以下:(a)活性化合物的独特特征和要实现的特定治疗效果,和(b)本领域组合这种活性化合物用以治疗个体敏感性中固有的局限性。
为了施用本发明的单特异性或多特异性分子药物缀合物,剂量范围为相对于宿主体重约0.0001mg/kg至100mg/kg,更通常为0.01mg/kg至50mg/kg。例如剂量可以是0.3mg/kg体重,1mg/kg体重,3mg/kg体重,5mg/kg体重或10mg/kg体重或在1-10mg/kg范围内。示例性的治疗方案需要每天施用、每周两次、每周一次、每两周一次、每三周一次、每四周一次、每月一次、每三个月一次或每三至六个月一次。本发明的单特异性或多特异性药物缀合物的优选施用方案包括通过静脉内施用1mg/kg体重或3mg/kg体重,使用以下施用方案之一给予单或多特异性药物缀合物:(i)每四周持续六个剂量,然后每三个月;(ii)每三周一次;(iii)3mg/kg体重一次,然后每3周1mg/kg体重。
可选地,单特异性或多特异性药物缀合物可以作为缓释制剂施用,在这种情况下需要较低的施用频率。剂量和频率的可根据单特异性或多特异性药物缀合物在患者体内的半衰期而有所不同。一般来说,人抗体的半衰期最长,其次是人源化抗体、嵌合抗体和非人抗体。给予的剂量和频率可以根据治疗是预防性的还是治疗性的而有所不同。在预防性应用中,在长时间内以相对不频繁的间隔施用相对低的剂量。一些患者在余生中持续接受治疗。在治疗应用中,有时需要在相对短的间隔时间内使用相对高的剂量,直到疾病的进展被减少或终止,优选是直到病人显示出部分或完全的疾病症状改善。此后,可以向患者施用预防方案。
本发明药物组合物中活性成分的实际剂量水平可变化,从而获得就特定患者、组合物、给予模式而言有效达到所需治疗响应而对患者没有毒性的活性成分量。所选剂量水平取决于多种药代动力学因素,包括所用的本发明特定组合物的活性、施用途径、施用时间、所用特定化合物的排泄率、治疗持续时间、与所用特定组合物联用的其他药物、化合物和/或材料、所治疗患者的年龄、性别、体重、病症、总体健康和既往病史、和医学领域熟知的其他因素。
本发明的单特异性或多特异性分子的“治疗有效剂量”优选地导致疾病症状严重程度的下降、疾病无症状期频率和持续时间的增加、或因疾病折磨而造成的损伤或残疾的预防。例如,对于肿瘤的治疗,相对于未治疗的受试者,“治疗有效剂量”优选抑制细胞生长或肿瘤生长或转移达至少约20%,更优选至少约40%,还更优选至少约60%,还更优选至少约80%。可以在预测人肿瘤功效的动物模型系统中评估药剂或化合物抑制肿瘤生长的能力。或者,组合物的这种性质可以通过检查化合物抑制的能力来评估,这种抑制在体外通过本领域技术人员已知的测定进行。治疗有效量的治疗化合物可以降低肿瘤大小、减少转移或改善受试者的症状。本领域普通技术人员将能够基于诸如受试者的体型、受试者症状的严重性和所选择的特定组合物或施用途径等因素来确定这样的量。
XII.施用
本发明的组合物可以使用本领域已知的多种方法中的一种或多种通过一种或多种施用途径来施用。如本领域技术人员所理解的,施用途径和/或方式将根据所需结果而变化。本发明抗体的优选施用途径包括静脉内、肌肉内、皮内、腹膜内、皮下、脊柱或其它胃肠外施用途径,例如通过注射或输注。这里所用的短语“肠胃外施用”是指除肠内和局部施用以外的施用方式,通常通过注射,包括但不限于静脉内、肌内、动脉内、鞘内、囊内、眶内、心内、皮内、腹腔内、经气管、皮下、表皮下、关节内、被膜下、蛛网膜下、脊柱内、硬膜外和胸骨内注射和输注。或者,本发明的单特异性或多特异分子缀合物可以通过非肠胃外途径施用,例如局部、表皮或粘膜施用途径,例如,鼻内、口服、阴道、直肠、舌下或局部施用。
活性化合物可以与载体一起制备,所述载体将保护化合物免于快速释放,例如控释制剂,包括植入物、透皮贴剂和微囊化递送系统。可以使用可生物降解的、生物相容的聚合物,例如乙烯乙酸乙烯酯、聚酐、聚乙醇酸、胶原、聚原酸酯和聚乳酸。许多制备这类制剂的方法已获得专利,或为本领域技术人员普遍所知。参见,例如,Sustained andControlled Release Drug Delivery Systems,J.R.Robinson,ed.,Marcel Dekker,Inc.,纽约,1978。
治疗组合物可以用本领域已知的医疗装置施用。例如,本发明的治疗组合物可以用无针皮下注射装置施用,例如US 5399163、US 5383851、US 5312335、US 5064413、US4941880、US 4790824和US 459655中公开的装置。用于本发明的众所周知的植入物和组件的实例包括US 4487603、US 4486194、US 4447233、US 4447224、US 4439196和US 4475196中所述的那些。这些专利通过引用并入本发明中。许多其他这样的植入物、递送系统和组件是本领域技术人员已知的。
XIII.治疗方法
一方面,本发明涉及使用上述单特异性或多特异性分子药物缀合物在体内治疗受试者,从而抑制癌性肿瘤的生长和/或转移。在一个实施方案中,本发明提供了抑制受试者中肿瘤细胞的生长和/或限制的方法,包括向受试者施用治疗有效量的单特异性或多特异性分子药物缀合物。
所治疗的优选癌症的非限制性实例包括慢性或急性白血病,包括急性骨髓性白血病、慢性骨髓性白血病、急性成淋巴细胞性白血病、慢性淋巴细胞性白血病,淋巴细胞性淋巴瘤,乳腺癌,卵巢癌,黑素瘤(例如转移性恶性黑素瘤),肾癌(例如透明细胞癌),前列腺癌(例如激素难治性前列腺癌),结肠癌和肺癌(例如非小细胞肺癌)。此外,本发明包括难治性或复发性恶性肿瘤,其生长可以被本发明的抗体抑制。可使用本发明的方法治疗的其它癌症的实例包括骨癌、胰腺癌、皮肤癌、头颈癌症、皮肤或眼内恶性黑素瘤、子宫癌、直肠癌、肛门区癌症、胃癌、睾丸癌、子宫癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌、霍奇金疾病、非霍奇金淋巴瘤、食管癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、儿童实体瘤、膀胱癌、肾或输尿管癌、肾盂癌、中枢神经系统(CNS)肿瘤、原发性中枢神经系统淋巴瘤、肿瘤血管发生、脊髓轴肿瘤、脑干神经胶质瘤、垂体腺瘤、Kaposi肉瘤、表皮样癌、鳞状上皮细胞癌症、T-细胞淋巴瘤、环境诱导的癌症包括石棉诱导的癌症,以及所述癌症的组合。
如本发明所用,术语“受试者”意在包括人和非人动物。非人动物包括所有脊椎动物,例如哺乳动物和非哺乳动物,如非人类灵长类动物、羊、狗、猫、牛、马、鸡、两栖动物和爬行动物,但哺乳动物是首选,如非人类灵长类动物、羊、狗、猫、牛和马。优选的受试者包括需要增强免疫应答的人类患者。该方法特别适用于治疗患有可通过增强免疫应答来治疗的病症的人类患者。
上述治疗也可以与标准的癌症治疗相结合。例如,它可以与化疗方案有效结合。在这些情况下,可以减少施用的化学治疗剂的剂量(Mokyr,M.等人,Cancer Res.,1998,58:5301-5304)。
可以使用用于激活宿主免疫反应性的其他抗体或与本发明的多特异性分子药物缀合物一起使用。所述抗体包括靶向树突细胞表面的分子,可激活DC功能和抗原呈递。例如,抗CD40抗体能够有效地替代T细胞辅助活性(Ridge,J.等人,Nature,1998,393:474-478),并且可以与本发明的多特异性分子药物缀合物组合使用(Ito,N.等人,Immunobiology,2000,201,527-540)。类似地,靶向T细胞共刺激分子例如CTLA-4(US5811097)、CD28(Haan,J.等人,Immunol.Lett.,2014,162,103-112)、OX-40(Weinberg,A.等人,J.Immunol.,2000,164,2160-2169)、4-1BB(Melero,I.等人,Nature Med.,1997,3,682-685)以及ICOS(Hutloff,A.等人,Nature,1999,397,262-266)的抗体或靶向PD-1(US8008449)和PD-L1(US 7943743;US 8168179)的抗体也可提供增加水平的T细胞活化。在另一个实例中,本发明的单特异性或多特异性分子药物缀合物可以与抗肿瘤抗体联合使用,例如RITUXAN(利妥昔单抗)、赫赛汀(曲妥单抗)、BEXXAR(托西莫单抗)、ZEVALIN(替伊莫单抗)、CAMPATH(阿仑单抗)、LYMPHOCIDE(依帕珠单抗)、阿瓦斯丁(贝伐单抗)和TARCEVA(埃罗替尼)等。
术语定义
如本发明所用,术语“烷基”是指烃链,通常长度为约1至25个原子。这种烃链优选但不一定是饱和的并且可以是带支链的或直链的,但通常直链是优选的。术语C1-10烷基包括具有1、2、3、4、5、6、7、8、9和10个碳的烷基。同样地,C1-25烷基包括具有1至25个碳原子的所有烷基。示例性烷基包括甲基、乙基、异丙基、正丁基、正戊基、2-甲基-1-丁基、3-戊基、3-甲基-3-戊基等。如本发明所用,当提到三个或更多个碳原子时,“烷基”包括环烷基。除非另有说明,烷基可以是取代的或未取代的。
如本发明所用,术语“官能团”是指在正常的有机合成条件下,可用于在其所连接的实体和通常携带其他官能团的另一实体之间形成共价键的基团。“双官能接头”是指具有两个官能团的,通过与缀合物的其他部分形成两个键的接头。
如本发明所用,术语“衍生物”是指具有额外结构部分的化学修饰化合物,其目的是引入新的官能团或调整原始化合物的性质。
如本发明所用,术语“保护基团”是指在某些反应条件下防止或阻断分子中特定化学反应性官能团反应的部分。各种保护基团在本领域是众所周知的,例如在T.W.Greene和G.M.Wuts,Protecting Groups in Organic Synthesis,第三版,Wiley,纽约,1999,和P.J.Kocienski,Protecting Groups,第三版,Thieme Chemistry,2003,以及其中引用的文献中都有描述。
如本发明所用,术语“PEG”是指聚乙二醇。用于本发明的聚乙二醇通常包含-(CH2CH2O)n-结构。聚乙二醇可以具有各种分子量、结构或几何形状。聚乙二醇基团可包含在典型的合成反应条件下不容易经历化学转化的封端基团。封端基团的实例包括-OC1-25烷基或-O芳基。
如本发明所用,术语“聚乙二醇化”是指聚乙二醇化学修饰。
如本发明所用,术语“接头”是指原子或原子集合,其用于连接相互连接部分,如抗体和聚合物分子。接头可以是可裂解的或不可裂解的。文献中描述了用于缀合物的各种接头的制备,包括例如GoldmacHer等人,Antibody-drug Conjugates and Immunotoxins:From Pre-clinical Development to THerapeutic Applications,第7章,in LinkerTechnology and Impact of Linker Design on ADC properties,Edited by PhillipsGL;Ed.Springer Science and Business Media,纽约(2013)。可裂解的接头包含可以在某些生物或化学条件下裂解的基团或部分。实例包括酶促裂解的二硫键、1,4-或1,6-苄基消除、三甲基锁定系统、基于N-二甘氨酸(bicine)的自裂解系统、酸不稳定的甲硅烷基醚接头和其他光不稳定的接头。
如本发明所用,术语“连接基团”或“连接基”是指连接化合物或缀合物的不同部分的官能团或部分。连接基团的例子包括但不限于:酰胺、酯、氨基甲酸酯、醚、硫醚、二硫化物、腙、肟和半氨基甲酸酯、碳二亚胺、酸不稳定基团、光不稳定基团、肽酶不稳定基团和酯酶不稳定基团。例如,接头部分和聚合物部分可以通过酰胺或氨基甲酸酯连接基团彼此连接。
如本发明所用,术语“肽”,“多肽”和“蛋白质”互换地用于描述聚合物中氨基酸残基的排列。除了稀有氨基酸和合成氨基酸类似物之外,肽、多肽或蛋白可以由标准的20种天然存在的氨基酸构成。它们可以是氨基酸的任何链,无论何种长度或翻译后修饰(例如,糖基化或磷酸化)。
“重组”肽、多肽或蛋白质是指通过重组DNA技术产生的肽、多肽或蛋白质;即,由编码所需肽的外源DNA构建体转化的细胞产生。“合成的”肽、多肽或蛋白质是指通过化学合成制备的肽、多肽或蛋白质。当提及例如细胞、或核酸、蛋白质或载体使用时,术语“重组”表示细胞、核酸、蛋白质或载体已通过引入异源核酸或蛋白质或天然核酸或蛋白质的改变而被修饰,或细胞来源于如此修饰的细胞。在本发明范围内包括含有一种或多种上述序列和异源序列的融合蛋白。异源多肽、核酸或基因源自外来物种,或者,如果来自相同物种,则基本上从其原始形式修饰。如果两个融合结构域或序列在天然存在的蛋白质或核酸中彼此不相邻,则它们彼此是异源的。
“分离的”肽、多肽或蛋白是指已经从与其天然结合的其它蛋白、脂质和核酸分开的肽、多肽或蛋白。多肽/蛋白可以构成纯化制剂干重的至少10%(即,10%至100%之间的任何百分比,例如20%、30%、40%、50%、60%、70%、80%、85%、90%、95%和99%)。纯度可以通过任何适当的标准方法测量,例如通过柱色谱法、聚丙烯酰胺凝胶电泳或HPLC分析。本发明中描述的分离的多肽/蛋白可以纯化自天然来源、通过重组DNA技术或通过化学方法产生。
“抗原”是指引发免疫反应或与该反应的产物结合的物质。术语“表位”是指抗体或T细胞结合的抗原区域。
如本发明所用,术语“抗体”包括整个抗体和任何抗原结合片段或其单链。整个抗体是糖蛋白,其包含至少通过二硫键连接的两条重(H)链和两条轻(L)链。每条重链包括重链可变区(VH)和重链恒定区。重链恒定区包括三个结构域:CH1,CH2和CH3。每条轻链包括轻链可变区(VL)和轻链恒定区(CL),轻链恒定区包括一个结构域。VH和VL区可以进一步细分为高变区,称为互补决定区(CDR),其间穿插着更加保守的区域,称为框架区(FR)。每个VH和VL由三个CDR和四个FR组成,从氨基端到羧基端按以下顺序排列:FR1,CDR1,FR2,CDR2,FR3,CDR3,FR4。重链可变区CDR和FR是HFR1,HCDR1,HFR2,HCDR2,HFR3,HCDR3,HFR4。轻链可变区CDR和FR是LFR1,LCDRl,LFR2,LCDR2,LFR3,LCDR3,LFR4。重链和轻链的可变区含有与抗原相互作用的结合结构域。抗体的恒定区可以介导免疫球蛋白与宿主组织或因子的结合,包括免疫系统的各种细胞(如效应细胞)和经典补体系统的第一组分(CIq)。
如本发明所用,“抗体片段”可以包含完整抗体的一部分,通常包括完整抗体的抗原结合区和/或可变区和/或抗体的保留FcR结合能力的Fc区。抗体片段的实例包括线性抗体;单链抗体分子;和由抗体片段形成的多特异性抗体。
如本发明所用,抗体的“抗原结合片段或部分”(或简称“抗体片段或部分”),是指保留了与抗原特异性结合能力的一个或多个抗体片段。已经表明,抗体的抗原结合功能可以通过全长抗体的片段进行。术语抗体的“抗原结合片段或部分”所包含的结合片段的实例包括:(i)Fab片段,由VL,VH,CL和CHI结构域组成的一价片段;(ii)F(ab′)2片段,包含在铰链区由二硫桥连接的两个Fab片段的二价片段;(iii)Fab′片段,基本上是带有部分铰链区的Fab;(iv)由VH和CHI结构域组成的Fd片段;(v)由抗体单臂的VL和VH结构域组成的Fv片段;(vi)dAb,其由VH结构域组成;(vii)单独的互补决定区(CDR);以及(viii)纳米抗体,其为包含一个可变结构域和两个恒定结构域的重链可变区。此外,尽管Fv片段的两个结构域VL和VH由单独的基因编码,但它们可以通过合成接头使用重组方法连接,该合成接头能够使它们成为VL和VH区配对的蛋白质单链,从而形成一价分子(称为单链Fv(scFv));参见例如Bird等人,Science 1988,242,423-426;以及Huston等人,Proc.Natl.Acad.Sci.USA 1988,85,5879-5883。此类单链抗体也意在包含在术语抗体的“抗原结合片段或部分”内。这些抗体片段使用本领域技术人员已知的常规技术获得,并且以与完整抗体相同的方式筛选使用。
如本发明所用,术语“Fc片段”或“Fc区”用于限定免疫球蛋白重链的C端区域。
如本发明使用的术语“单克隆抗体”是指从基本同源抗体的群体获得的抗体,即构成该群体的单个抗体除了可能少量存在的可天然发生的突变以外是相同的。单克隆抗体具有高度的特异性,针对单一抗原位点。此外,与通常包括针对不同决定簇(表位)的不同抗体的常规(多克隆)抗体制剂相反,各单克隆抗体针对抗原上的单个决定簇。修饰语“单克隆”表明从基本同源的抗体群体获得的抗体的特征,并不理解为需要通过任何特定的方法来产生该抗体。例如,本发明使用的单克隆抗体可以通过Kohler和Milstein(Kohler,G.等人,Nature,1975,256,495-497)首先描述的杂交瘤方法制备,其通过引用并入本发明中,或可以通过重组DNA方法(US 4816567)制备,其通过引用并入本发明。单克隆抗体还可以通过使用例如Clackson等人,Nature,1991,352,624-628,和Marks等人,J Mol Biol,1991,222,581-597中描述的技术从噬菌体抗体文库中分离,各文献通过引用并入本发明中。
本发明的单克隆抗体特别包括“嵌合”抗体,其中重链和/或轻链的一部分与源自特定物种或属于特定抗体类型或亚类的抗体中的相应序列相同或同源,而该链中的剩余部分与源自另一物种或属于另一抗体类型或亚类的抗体及这些抗体的片段中的相应序列相同或同源,只要它们表现出所需的生物学活性即可(参见美国专利号4,816,567;Morrison等人,Proc Natl Acad Sci USA,1984,81,6851-6855;Neuberger等人,Nature,312,1984,604-608;Takeda等人,Nature,1985,314,452-454;国际专利申请号PCT/GB85/00392,其各通过引用并入本发明中)。
非人(例如鼠)抗体的“人源化”形式是包含源自非人免疫球蛋白的最少序列的嵌合抗体。对于绝大部分而言,人源化抗体是人免疫球蛋白(受体抗体),其中来自受体的超变区的残基被来自非人物种(供体抗体)的具有期望的特异性、亲和力和能力的超变区的残基取代,所述非人物种如小鼠、大鼠、兔或非人灵长类动物。在某些情况下,人免疫球蛋白的Fv框架区(FR)残基被相应的非人残基所取代。此外,人源化抗体可以包含未在受体抗体或供体抗体中出现的残基。进行这些修饰来进一步优化抗体的性能。通常,人源化抗体包括至少一个且通常两个可变域的基本全部,其中所有或基本所有的超变环对应于非人免疫球蛋白的那些超变环,并且所有或基本所有的FR残基是人免疫球蛋白序列的那些残基。任选地,人源化抗体还包含免疫球蛋白恒定区(Fc)的至少一部分,通常是人免疫球蛋白的恒定区(Fc)。进一步细节可以参见Jones等人,Nature,1986,321,522-525;Riechmann等人,Nature,1988,332,323-329;Presta,Curr Op Struct Biol,1992,2,593-596;美国专利号5,225,539,其各通过引用并入本发明中。
“人抗体”是指具有完全人序列的任何抗体,例如可以从人杂交瘤、人噬菌体展示文库或表达人抗体序列的转基因小鼠获得。
术语“药物组合物”是指活性剂与惰性或活性的载体的组合,使得该组合物特别适合于体内或离体的诊断或治疗用途。
如本发明所用,“药学上可接受的载体”包括生理上相容的任何和所有溶剂、分散介质、包衣、抗细菌剂和抗真菌剂、等渗剂和吸收延迟剂等。“药学上可接受的载体”在施用于受试者或施用于受试者后不会引起不期望的生理作用。药物组合物中的载体必须是“可接受的”,也意味着它与活性成分相容并且能够使其稳定。一种或多种增溶剂可用作药物载体以递送活性剂。药学上可接受的载体的实例包括但不限于生物相容性载体、佐剂、添加剂和稀释剂,以获得可用作剂型的组合物。其他载体的实例包括胶体氧化硅、硬脂酸镁、纤维素和十二烷基硫酸钠。Remington′s Pharmaceutical Sciences描述了其他合适的药物载体和稀释剂,以及它们使用的药物必需品。优选地,载体适用于静脉内、肌肉内、皮下、肠胃外、脊柱或表皮施用(例如,通过注射或输注)。治疗化合物可包括一种或多种药学上可接受的盐。“药学上可接受的盐”是指保留母体化合物的所需生物活性并且不会产生任何不期望的毒理学作用的盐(参见例如,Berge,S.M.等人,J.Pharm.Sci.1997,66:1-19)。
如本发明所用,“治疗”或“处理”是指向患有疾病或有发展疾病风险的受试者施用化合物或药剂,目的是治愈、缓解,减轻、补救、延缓其发作、预防或改善疾病、疾病的症状、继发于疾病的疾病状态或对疾病的易感性。
“有效量”是指赋予治疗对象治疗效果所需的活性化合物/药剂的量。如本领域技术人员所认识到的,有效剂量将根据所治疗病症的类型、施用途径、赋形剂的使用以及与其他治疗性治疗共同使用的可能性而变化。治疗肿瘤病症的治疗有效量的组合是与未治疗的动物相比将导致例如肿瘤尺寸减小、肿瘤灶数量减少或肿瘤生长减慢。
如本发明所公开的,提供了一些数值的范围。应当理解,除非上下文另有明确规定,否则还具体公开了该范围的上限和下限之间的每个中间值,至下限单位的十分之一。在所述范围内的任何规定值或中间值与所述范围内的任何其他陈述或中间值之间的每个较小范围都包含在本发明内。这些较小范围的上限和下限可以独立地包括在该范围内或排除在该范围外,并且在较小范围内包括任一个、零个或两个限制的每个范围也包括在本发明内,受制于规定的范围内任何特别排除的限制。在所述范围包括一个或两个限制的情况下,排除那些包括的限制之一或两者的范围也包括在本发明中。
术语“约”通常是指所示数字的加或减10%。例如,“约10%”可表示9%至11%的范围,而“约1”可表示0.9至1.1。从上下文中可以明显看出″约″的其他含义,如四舍五入,因此,例如“约1”也可以表示从0.5至1.4。
实施例
下面的实施例有助于进一步了解本发明,但不意味着以任何方式限制本发明的有效范围。
实施例1:30kmPEG-Lys(Mal)-(Val-Cit-PAB-MMAE)4的制备
带支链接头中间体化合物7的制备(图1)
在氩气、室温下,向1(3.1g,10mmol)的干燥CH2Cl2(50mL)溶液中加入2(2.6g,12mmol,1.2当量)、EDCI(2.87g,15mmol,1.5当量)和HOBt(0.27g,2mmol,0.2当量)。搅拌该混合物,直到通过TLC观察到完全转化。反应完成后,用CH2Cl2萃取混合物,有机层用盐水洗涤,用Na2SO4干燥,过滤并在真空中浓缩。在硅胶上通过色谱纯化粗反应混合物,得到产物3。
在氩气、室温下,向3(2.6g,5mmol)的THF(50mL)溶液中加入1M LiOH(20mL,20mmol,4.0当量)。搅拌该混合物,直到通过TLC观察到完全转化。反应完成后,用CH2Cl2提取混合物,有机层用盐水洗涤,用Na2SO4干燥,过滤并在真空中浓缩。在硅胶上通过色谱纯化粗反应混合物,得到产物4。
在氩气、室温下,向4(2.3g,5mmol)的干燥CH2Cl2(50mL)溶液中加入5(1.6g,6mmol,1.2当量)、EDCI(1.4g,7.5mmol,1.5当量)和HOBt(0.14g,1mmol,0.2当量)。搅拌该混合物,直到通过TLC观察到完全转化。反应完成后,用CH2Cl2萃取混合物,有机层用盐水洗涤,用Na2SO4干燥,过滤并在真空中浓缩。在硅胶上通过色谱纯化粗反应混合物,得到产物6。
将二乙胺(1.0mL)加入到6(0.97g,1.0mmol)的DMF(10mL)溶液中,反应在室温下进行1.5小时。在不超过30℃的浴温下真空除去二乙胺和溶剂。将残余物用乙醚(25mL)研磨。收集沉淀的固体,过滤并用乙醚洗涤两次(2×20mL)并真空干燥,得到产物7。
化合物14 Val-Cit-PAB-MMAE的制备(图2)
将Fmoc-Val-OH 8(3.4g,10mmol,1.0当量)、N-羟基琥珀酰亚胺(1.5g,13mmol,1.3当量)在0℃下溶于CH2Cl2(60mL)和THF(20mL)的混合物中,并将EDCI(2.5g,13mmol,1.3当量)加入上述溶液。然后将溶液缓慢温热至室温。反应混合物在室温下搅拌,直到反应完成。然后在减压下浓缩反应混合物。浓缩残余物用THF溶解并过滤以除去EDU。浓缩滤液并在5-10℃下用正庚烷重新浆化12小时。过滤固体,清洗并在真空下干燥,得到Fmoc-Val-OSu。
将Fmoc-Val-OSu(4.4g,10mmol,1.0当量)在室温下溶解在乙腈(50mL)中,然后加入碳酸钠(1.2g,11mmol,1.1当量)和L-瓜氨酸(1.9g,11mmol,1.1eq)在水(50mL)中的溶液。反应混合物在35℃下搅拌数小时,直到反应完成。混合物冷却至20℃,用15%柠檬酸(150mL)淬灭,并用EtOAc/i-PrOH(9∶1)(200mL x2)萃取。合并的有机相用水(140mL)洗涤后,用无水Na2SO4干燥并浓缩。残余物用甲基叔丁基醚洗涤,得到Fmoc-Val-Cit-OH 9。
将Fmoc-Val-Cit-OH 9(3.0g,6.0mmol,1.0当量)和4-氨基苄醇(1.5g,12.1mmol,2.0当量)溶解在CH2Cl2(70mL)和MeOH(30mL)的溶液中。加入EEDQ(3.0g,12.1mmol,2.0当量),将溶液在室温下搅拌1天。加入额外的EEDQ(1.5g,6.0mmol,1.0当量),并将溶液持续搅拌12小时。浓缩反应混合物,残余物用甲基叔丁基醚洗涤,得到Fmoc-Val-Cit-PAB-OH 10。
向Fmoc-Val-Cit-PAB-OH 10(2.0g,3.3mmol,1.0当量)的DMF(20mL)溶液中加入对硝基苯甲酰氯11(1.2g,6.6mmol,2.0当量)和吡啶(0.4mL,5.0mmol,1.5当量)。反应混合物在室温下搅拌12小时并浓缩。残余物用EtOAc/甲基叔丁基醚洗涤,得到产物12。
在室温下,向12(1.3g,1.7mmol,1.0当量)的DMF(3.4mL)溶液中加入HOBt(376mg,2.78mmL,1.6当量)和吡啶(0.85ml),随后加入MMAE(1.0g,1.39mmol)。溶液在室温下搅拌24小时。浓缩反应混合物,残余物在硅胶上通过色谱纯化,得到产物Fmoc-Val-Cit-PAB-MMAE13。
向Fmoc-Val-Cit-PAB-MMAE 13(1.4g,1.1mmol)的DMF(20mL)溶液中加入Et2NH(5mL),溶液在室温下搅拌12小时。浓缩反应混合物,残余物用EtOAc/甲基叔丁基醚洗涤,得到产物14。
化合物19 30k mPEG-Lys(Mal)-(MMAE)4的制备(图3)
将H-Lys(boc)-OH(369mg,1.5mmol,3.0当量)加入100mL无水DMF中,然后加入DIEA(5.0mmol,10.0当量),化合物15(15g,0.5mmol,1.0当量)和150mL无水CH2Cl2。混合物在氩气下室温搅拌过夜。滤出不溶性材料。除去溶剂,残余物从CH2Cl2/甲基叔丁基醚重结晶。分离的固体再次从ACN/2-丙醇重结晶。将产物在40℃下真空干燥4小时,得到产物16。
在氩气、室温下,向16(15g,0.5mmol)的干燥CH2Cl2(150mL)溶液中加入7(1.1g,1.5mmol,3.0当量)、EDCI(0.58g,3.0mmol,6.0当量)和HOBt(0.61g,4.5mmol,9.0当量)。混合物在氩气下室温搅拌过夜。除去溶剂,残余物从CH2Cl2/甲基叔丁基醚重结晶。沉淀的固体再次从ACN/2-丙醇重结晶。将产物在40℃下真空干燥4小时,得到产物17。
将17(9.0g,0.3mmol)溶于CH2Cl2(90mL)中,然后加入TFA(45mL)。混合物在室温下搅拌1小时。在<35℃下尽可能的真空除去溶剂。残余物从CH2Cl2/甲基叔丁基醚重结晶两次。将产物在40℃下真空干燥生成中间体。然后在氩气下将干燥的中间体(6.0g,0.2mmol,1.0当量)溶于无水CH2Cl2(60mL)中。将溶液冷却至0-5℃,在0-5℃下加入DIPEA(517mg,4mmol,20当量)和NHS-PEG2-Mal(0.22g,0.5mmol,2.5当量)。将混合物在0-5℃下搅拌2小时,然后使其缓慢加热至室温并在氩气下保持室温过夜。反应之后,除去溶剂,残余物从CH2Cl2/甲基叔丁基醚重结晶。沉淀的固体再次从ACN/2-丙醇重结晶。将分离的产物在40℃下真空干燥4小时,得到产物18。
在氩气、室温下,向18(3.0g,0.1mmol)的干燥CH2Cl2(30mL)溶液中加入14(0.9g,0.8mmol,8.0当量)、EDCI(0.46g,2.4mmol,24当量)和HOBt(0.49g,3.6mmol,36当量)。混合物在氩气下室温搅拌过夜。除去溶剂,残余物从CH2Cl2/甲基叔丁基醚重结晶。沉淀的固体再次从ACN/2-丙醇重结晶。将分离的产物在40℃下真空干燥4小时,得到产物19。
实施例2:SCAHer2xSCAHer2的制备
抗Her2(SCAHer2)-1和抗Her2(SCAHer2)-2的双特异性单链抗体(SCA)片段可以通过哺乳动物细胞(例如,使用EasySelectTM的CHO)或酵母(例如,含有pPICZ载体的毕赤酵母表达试剂盒)中的重组DNA技术制备。合成对应于如下(SEQ ID NO:1)氨基酸序列的SCAHer2-1xSCAH2-2的DNA序列并将其克隆到表达载体中并在宿主细胞中转化。表达的蛋白质通过Ni螯合树脂或蛋白质L树脂纯化。为促进随后的缀合,通过重组DNA技术将位点特异性缀合官能团硫醇插入两个Her2 SCA之间的接头中。
SCAHer2IIxSCAHer2IV的氨基酸序列(SEQ ID NO:1):
实施例3:30kmPEG-(SCAHer2xSCAHer2)-(Val-Cit-PAB-MMAE)4的制备(图4)
在室温下使用还原剂TCEP-HCl的PBS缓冲液(pH=7.4)将蛋白质SCAHer2/SCAHer2处理30分钟,然后用pH=4.12的500mM磷酸钠的储液将pH调节至pH 6.8。在聚乙二醇化之前将处理的蛋白质浓缩至5mg/mL。SCAHer2/SCAHer2的聚乙二醇化使用5至10摩尔当量的化合物19[30kmPEG-Lys(Mal)-(Val-Cit-PAB-MMAE)4]在室温下进行3小时。将反应在室温下用10mM的L-胱氨酸淬灭10分钟。最终产物PEG-Lys(SCAHer2/SCAHer2)-(Val-Cit-PAB-MMAE)4用阳离子交换色谱柱(CM快流)在pH 6.5下的20mM磷酸盐缓冲液中纯化。通过SEC-HPLC和基于细胞的活性测定来证实目标化合物20。
实施例4:Val-Cit-PABC-MMAE的制备(图5)
Fmoc-Val-OSu(化合物2):将Fmoc-Val-OH(20.3g,60.0mmol)和N-羟基琥珀酰亚胺亚胺(9.0g,78.0mmol)溶解在CH2Cl2(120mL)和THF(40mL)的混合物中。另外,将EDCI(13.8g,72.0mmol)溶于CH2Cl2(200mL)中,并将溶液冷却至0-5℃。然后将Fmoc-Val-OH/NHS溶液加入到EDCI溶液中,随后将反应混合物升温至室温。反应混合物在室温下搅拌,直到反应完成。然后尽可能地减压浓缩反应混合物,将残余物CH2Cl2用THF(2×100mL)螯合。浓缩的残余物用THF(800mL)溶解并过滤以除去EDU。滤液减压浓缩,残余物用正庚烷(800mL)在5-10℃下浆化12小时。将固体过滤、洗涤并真空干燥,得到呈白色粉末的Fmoc-Val-OSu(2)(23.8g,91%)。HRMS(ESI)对C24H24N2O6Na[M+Na]+的计算值为459.1532,实测值为459.1523。
Fmoc-Val-Cit(化合物3):将Fmoc-Val-Osu(9.8g,22.5mmol)在室温下溶于DME(150mL)中。另外,在室温下将碳酸氢钠(2.1g,24.7mmol)溶解在水(150mL)中,然后加入L-瓜氨酸(4.3g,24.7mmol),得到均匀的澄清溶液。然后将制备的L-瓜氨酸溶液加入到Fmoc-Val-Osu溶液中。加入THF(75mL),反应混合物在室温下搅拌16小时,直到反应完成。将反应混合物用15%柠檬酸(200mL)酸化并用旋转蒸发仪(Rotavapor)浓缩。残余物在水(500mL)中悬浮2小时,然后过滤并在真空中干燥。将干燥的固体重新悬浮在甲基叔丁基醚(500mL)中,搅拌12小时后过滤、洗涤并真空干燥,得到呈白色粉末的Fmoc-Val-Cit(3)(6.8g,61%)。HRMS(ESI)对C26H33N4O6[M+H]+的计算值为497.2400,实测值为497.2388。
Fmoc-Val-Cit-PABOH(化合物4):将EEDQ(4.95g,20.0mmol)加入化合物3(4.96g,10.0mmol)和4-氨基苄醇(2.46g,20.0mmol)的CH2Cl2(350mL)和MeOH(150mL)溶液中。将反应混合物在室温下搅拌24小时。将另外的EEDQ(2.5g,10.0mmol)加入到反应中,并将混合物再搅拌24小时。反应完成后,减压除去溶剂,并将所得残余物在甲基叔丁基醚(800mL)中浆化12小时。过滤固体、洗涤并真空干燥,得到呈白色粉末的化合物4(4.1g,69%)。HRMS(ESI)对C33H40N5O6[M+H]+的计算值为602.2979,实测值为602.2969。
Fmoc-Val-Cit-PABC-PNP(化合物5):在室温下向化合物4(5.2g,8.6mmol)和双(4-硝基苯基)碳酸酯(4.9g,16.1mmol)的DMF(52mL)溶液中加入DIPEA(2.5mL,15.0mmol)。反应混合物在室温下搅拌5小时,直到反应完成。通过加入无水乙酸乙酯(250mL)和甲基叔丁基醚(250mL)使产物沉淀。将悬浮液冷却至0℃并搅拌30分钟。通过过滤分离固体,洗涤并真空干燥,得到呈浅黄色粉末的Fmoc-Val-Cit-PABC-PNP(5)(4.7g,72%)。HRMS(ESI)对C40H43N6O10[M+H]+的计算值为767.3041,实测值为767.3045。
Fmoc-Val-Cit-PABC-MMAE(化合物6):将化合物MMAE(2.0g,1.8mmol)和Fmoc-Val-Cit-PABC-PNP(5)(2.8g,3.6mmol)溶于DMF(20mL)。然后加入HOBt(0.75g,5.6mmol)和吡啶(1.7mL),将反应混合物在室温下搅拌24小时。反应完成后,将反应混合物冷却至0℃,然后加入甲基叔丁基醚(180mL)以沉淀产物。将浆液搅拌3-5小时并过滤,洗涤并在真空下干燥。通过柱纯化纯化粗产物,得到呈黄色粉末的Fmoc-Val-Cit-PABC-MMAE(6)(3.0g,80%)。HRMS(ESI)对C73H105N10O14[M+H]+的计算值为1345.7812,实测值为1345.7820。
Val-Cit-PABC-MMAE(化合物7):将化合物6(3.0g,2.2mmol)悬浮在无水DMF(40mL)中并在室温下搅拌直至形成均匀的悬浮液。然后加入二乙胺(10mL)并将反应混合物在室温下搅拌3小时。反应完成后,在60分钟内加入甲基叔丁基醚(100mL)和乙酸乙酯(50mL)。所得混合物在0℃下搅拌4小时。过滤固体并真空干燥,得到呈淡黄色粉末的Val-Cit-PABC-MMAE(7)(2.3g,92%)。HRMS(ESI)对C58H95N10O12[M+H]+的计算值为1123.7131,实测值为1123.7142。
实施例5:化合物13(具有2XMMAE的带支链接头B)的制备(图6)
化合物10:在氩气、室温下,向化合物8(0.62g,2.0mmol)的干燥CH2Cl2(15mL)溶液中加入3,3′-氮杂二基二丙酸二叔丁酯(9)(0.62mL,2.2mmol)、EDCI(0.58g,3.0mmol)和HOBt(54mg,0.4mmol)。反应混合物在室温下搅拌并通过TLC监测。反应完成后,用CH2Cl2(30mL x 2)萃取混合物,合并有机层,用盐水(20mL)洗涤并用Na2SO4干燥。使用旋转蒸发仪浓缩溶液。在硅胶上通过色谱纯化粗反应混合物,得到无色油状的产物10(1.1g,96%)。HRMS(ESI)对C32H43N2O7[M+H]+的计算值为567.3070,实测值为567.3062。
化合物11:将化合物10(5.2g,9.2mmol)溶于CH2Cl2(100mL),然后加入TFA(25mL)。混合物在室温下搅拌3小时。在<35℃下尽可能的真空除去溶剂。在硅胶上通过色谱纯化残余物,得到无色油状的产物11(3.4g,83%)。HRMS(ESI)对C24H27N2O7[M+H]+的计算值为455.1818,实测值为455.1824。
化合物12:在氩气、室温下,向化合物11(41mg,0.091mmol)的干燥CH2Cl2(2mL)和DMF(2mL)搅拌溶液中加入Val-Cit-PABC-MMAE(7)(224mg,0.2mmol)、EDCI(52mg,0.27mmol)和HOBt(5mg,0.04mmol)。反应混合物在室温下搅拌并通过TLC监测。反应完成后,将混合物真空浓缩。使用预制的带有Welch Ultimate XB-C18柱子(洗脱液:A=0.1%TFA溶于水,B=MeCN)的HPLC纯化残余物,得到呈淡黄色固体的化合物12(74mg,31%)。HRMS(ESI)对C140H212N22O29[M+2H]2+的计算值为1333.2912,实测值为1333.2907。
化合物13:将二乙胺(0.6mL)加入化合物12(73mg)的DMF(3mL)溶液中。使反应在室温下进行4小时。使用旋转蒸发仪浓缩反应混合物,使用预制的带有Welch Ultimate XB-C18柱子(洗脱液:A=0.1%TFA溶于水,B=MeCN)的HPLC纯化残余物,得到呈淡黄色固体的化合物13(71mg,99%)。HRMS(ESI)对C125H202N22O27[M+H]+的计算值为1222.2572,实测值为1222.2560。
实施例6:化合物18(具有2XMMAE的带支链接头B)的制备(图7)
化合物15:在氩气、室温下,向化合物14(0.68g,2.0mmol)的干燥CH2Cl2(10mL)溶液中加入3,3′-氮杂二基二丙酸二叔丁酯(9)(0.64mL,2.2mmol)、EDCI(0.58g,3.0mmol)和HOBt(54mg,0.4mmol)。反应混合物在室温下搅拌并通过TLC监测。反应完成后,用CH2Cl2(2X30mL)萃取混合物,合并的有机层用盐水(20mL)洗涤并用Na2SO4干燥,用旋转蒸发仪过滤浓缩。在硅胶上通过色谱纯化残余物,得到无色油状的产物15(1.2g,99%)。HRMS(ESI)对C34H47N2O7[M+H]+的计算值为595.3383,实测值为595.3380。
化合物16:将化合物15(0.5g,0.84mmol)溶于CH2Cl2(6.0mL),然后加入TFA(3.0mL)。混合物在室温下搅拌3小时。在<35℃下尽可能的真空除去溶剂。在硅胶上通过色谱纯化残余物,得到无色油状的产物16(0.34g,85%)。HRMS(ESI)对C26H31N2O7[M+H]+的计算值为483.2131,实测值为483.2127。
化合物17:在氩气、室温下,向化合物16(185mg,0.383mmol)的干燥CH2Cl2(8mL)和DMF(8mL)混合物溶液中加入Val-Cit-PABC-MMAE(7)(947mg,0.843mmol)、EDCI(238mg,1.23mmol)和HOBt(26mg,0.19mmol)。反应混合物在室温下搅拌并通过HPLC监测。反应完成后,混合物用旋转蒸发仪浓缩。使用预制的带有Welch Ultimate XB-C18柱子(洗脱液:A=0.1%TFA溶于水,B=MeCN)的HPLC纯化残余物,得到呈淡黄色固体的化合物17(0.56g,54%)。HRMS(ESI)对C142H216N22Q29[M+H]+的计算值为2694.6137,实测值为2694.6146。
化合物18:将二乙胺(2mL)加入化合物17(0.62g)的DMF(5mL)溶液中。反应混合物在室温下进行2小时。使用旋转蒸发仪浓缩反应混合物,使用预制的带有Welch UltimateXB-C18柱子(洗脱液:A=0.1%TFA溶于水,B=MeCN)的HPLC纯化残余物,得到呈淡黄色固体的化合物18(0.51g,89%)。HRMS(ESI)对C127H205N22O27[M+H]+的计算值为2471.5378,实测值为2471.5369;对C127H206N22O27[M+2H]2+的计算值为1236.2728,实测值为1236.2744。
实施例7:化合物22(具有4XMMAE的带支链接头B)的制备(图8)
化合物20:在氩气、室温下,向化合物19(0.76g,2.0mmol)的干燥CH2Cl2(10mL)溶液中加入3,3′-氮杂二基二丙酸二叔丁酯(9)(0.64mL,2.2mmol)、EDCI(0.58g,3.0mmol)和HOBt(54mg,0.4mmol)。反应混合物在室温下搅拌并通过TLC监测。反应完成后,用CH2Cl2(2X30mL)萃取混合物,合并的有机层用盐水(20mL)洗涤并用Na2SO4干燥,用旋转蒸发仪过滤浓缩。在硅胶上通过色谱纯化粗反应混合物,得到无色油状的产物20(1.2g,99%)。HRMS(ESI)对C29H55N4O11[M+H]+的计算值为635.3867,实测值为635.3860。
化合物21:将化合物20(0.3g,0.47mmol)溶于CH2Cl2(4.0mL),然后加入TFA(2.0mL)。混合物在室温下搅拌3小时。在<35℃下尽可能的真空除去溶剂。在硅胶上通过色谱纯化残余物,得到无色油状的产物21(0.34g,85%)。HRMS(ESI)对C21H39N4O11[M+H]+的计算值为523.2615,实测值为523.2607。
化合物22:在氩气、室温下向化合物21(39mg,0.076mmol)的干燥CH2Cl2(2mL)和DMF(2mL)混合物搅拌溶液中加入化合物18(0.41g,0.17mmol)、EDCI(43mg,0.23mmol)和HOBt(4.0mg,0.03mmol)。反应混合物在室温下搅拌并通过HPLC监测。反应完成后,混合物用旋转蒸发仪浓缩。使用预制的带有Welch Ultimate XB-C18柱子(洗脱液:A=0.1%TFA溶于水,B=MeCN)的HPLC纯化残余物,得到呈淡黄色固体的化合物22(81mg,20%)。HRMS(ESI)对C275H445N48O63[M+3H]3+的计算值为1810.1053,实测值为1810.1061。对C275H446N48O63[M+4H]4+的计算值为1357.8310,实测值为1357.8346.
实施例8:化合物27(具有4XMMAE的带支链接头B)的制备(图9)
化合物24:在氩气、室温下,向化合物21(0.57g,1.1mmol)的干燥CH2Cl2(10mL)溶液中加入化合物23(0.51g,2.4mmol)、EDCI(0.67g,3.5mmol)、HOBt(74mg,0.55mmol)和DIPEA(0.78mL,4.4mmol)。反应混合物在室温下搅拌并通过TLC监测。反应完成后,用CH2Cl2(2x30mL)萃取混合物,合并的有机层用盐水(20mL)洗涤并用Na2SO4干燥,用旋转蒸发仪过滤浓缩。在硅胶上通过色谱纯化残余物,得到无色油状的产物24(0.7g,79%)。HRMS(ESI)对C39H73N6O13[M+H]+的计算值为833.5236,实测值为833.5231。
化合物25:将化合物24(0.52g,0.62mmol)溶于CH2Cl2(5.0mL),然后加入TFA(2.0mL)。混合物在室温下搅拌3小时。在<35℃下尽可能的真空除去溶剂。在硅胶上通过色谱纯化残余物,得到无色油状的产物25(0.42g,93%)。HRMS(ESI)对C31H57N6O13[M+H]+的计算值为721.3984,实测值为721.3997。
化合物26:在氩气、室温下,向化合物25(77mg,0.11mmol)的DMF(2mL)溶液中加入化合物18(0.58g,0.24mmol)、EDCI(82mg,0.43mmol)和HOBt(14mg,0.11mmol)。反应混合物在室温下搅拌并通过HPLC监测。反应完成后,混合物用旋转蒸发仪浓缩。使用预制的带有Welch Ultimate XB-C18柱子(洗脱液:A=0.1%TFA溶于水,B=MeCN)的HPLC纯化粗反应混合物,得到呈淡黄色固体的化合物26(0.23g,38%)。HRMS(ESI)对C285H463N50O65[M+3H]3+的计算值为1876.4854,实测值为1876.4851。对C285H464N50O65[M+4H]4+的计算值为1407.6160,实测值为1407.6158。
化合物27:将Lindlar催化剂(130mg,5重量%)加入叠氮化物26(180mg,0.03mmol)的甲醇(10mL)搅拌溶液中。将反应烧瓶抽空并用氢气冲洗。反应混合物在氢气环境(气球)下室温搅拌5小时。反应完成后,通过Celite垫过滤催化剂,用甲醇(10mL)洗涤滤饼,减压浓缩滤液。使用预制的带有Welch Ultimate XB-C18柱子(洗脱液:A=0.1%TFA溶于水,B=MeCN)的HPLC纯化残余物,得到呈淡黄色固体的化合物27(130mg,74%)。HRMS(ESI)对C285H465N48O65[M+3H]3+的计算值为1867.8219,实测值为1867.8217。对C285H466N48O65[M+4H]4+的计算值为1401.1184,实测值为1401.1181。
实施例9:化合物32(30kmPEG(马来酰亚胺)-2MMAE)的制备(图10)
化合物29:将H-Lys(boc)-OH(369mg,1.5mmol)加入无水DMF(100mL)中,然后加入DIPEA(0.83mL,5.0mmol)、化合物28(15g,0.5mmol)和无水CH2Cl2(150mL)。混合物在氩气下室温搅拌过夜。滤出不溶性材料。除去溶剂,残余物从CH2Cl2/甲基叔丁基醚(45mL/300mL)重结晶。分离的固体从MeCN/2-丙醇(30mL/450mL)重结晶。将产物在40℃下真空干燥4小时,得到呈白色粉末的产物29(13.6g,91%)。13C-NMR(126MHz,CDCl3)δ172.74,155.65,155.55,78.41,70.13(PEG),63.66,58.55,52.99,39.90,31.70,29.17,28.08,21.97。
化合物30:将TFA(29.5mL)加入化合物29(5.7g,0.19mmol)的57mL无水CH2Cl2(57mL)溶液中。混合物在室温下搅拌1小时。在<35℃下尽可能的真空除去溶剂。残余物从CH2Cl2/甲基叔丁基醚(14.5mL/115mL)重结晶两次。将分离产物在40℃下真空干燥,得到呈白色粉末的产物30(4.7g,84%)。
化合物31:在0℃下,将DIPEA(473mg,3.6mmol)加入化合物30(5.5g,0.18mmol)的无水CH2Cl2(55mL)搅拌溶液中,然后加入NHS-PEG2-Mal(0.2g,0.47mmol)。将混合物在0℃下搅拌1.5小时,然后将溶液从0℃缓慢加热至室温并在氩气下搅拌过夜。除去溶剂,残余物从CH2Cl2/甲基叔丁基醚(13.8mL/110mL)重结晶。分离的固体再次从MeCN/2-丙醇(11mL/165mL)重结晶。固体在真空下干燥,得到呈白色粉末的化合物31(5.0g,90%)。13C-NMR(126MHz,CDCl3)δ172.76,171.46,170.01,169.94,155.55,133.82,71.37,70.01(PEG),69.05,68.92,66.49,63.53,58.44,52.92,38.65,36.01,33.84,33.71,31.36,28.21,21.85。
化合物32:在氩气、室温下,向在DMF/CH2Cl2(5mL/5mL)混合溶剂中的化合物31(0.76g,0.025mmol)搅拌溶液中加入化合物13(0.12g,0.05mmol)、DCC(31mg,0.15mmol)和DMAP(28mg,0.23mmol)。反应混合物在室温下搅拌并通过HPLC监测。反应完成后,混合物用旋转蒸发仪浓缩。使用预制的带有PhenomenexC18柱子(洗脱液:A=0.1%TFA溶于水,B=MeCN)的HPLC纯化残余物,得到呈白色固体的化合物32(0.36g,47%)。MS(MALDI-TOF)m/z 33863。
实施例10:化合物35(20kmPEG(马来酰亚胺)-4MMAE)的制备(图11)
化合物33:化合物33的合成参考化合物31的制备。
化合物34:在氩气、室温下,向化合物33(2.0g,0.1mmol)的无水CH2Cl2(20mL)搅拌溶液中加入DBCO-NH2(83mg,0.3mmol)、EDCI(115mg,0.6mmol)和HOBt(122mg,0.9mmol)。反应混合物在室温下搅拌并通过HPLC监测。除去溶剂,残余物从CH2Cl2/甲基叔丁基醚(5mL/40mL)重结晶。分离的固体再次从MeCN/2-丙醇(4mL/60mL)重结晶。将所得固体在40℃下真空干燥4小时,得到呈白色粉末的产物34(1.9g,89%)。13C-NMR(214MHz,CDCl3)δ171.12,171.08,170.05,169.75,155.64,150.59(d,J=21.4Hz),147.54(d,J=6.6Hz),133.82,131.69(d,J=13.8Hz),128.70,128.27(d,J=11.3Hz),127.93(d,J=5.4Hz),127.79,127.39(d,J=8.3Hz),126.66,125.04(d,J=6.0Hz),122.46(d,J=4.9Hz),121.85(d,J=11.3Hz),114.21(d,J=9.8Hz),107.38(d,J=33.6Hz),70.06(PEG),66.59,63.64(d,J=7.3Hz),58.50,54.97(d,J=13.3Hz),54.23(d,J=59.1Hz),38.61,38.40,36.31,34.86(d,J=18.0Hz),34.05(d,J=20.8Hz),33.89,33.78,31.76(d,J=40.2Hz),28.31(d,J=9.8Hz),21.99(d,J=17.1Hz)。
化合物35:将化合物34(147mg,0.007mmol)溶于无水MeOH(3mL),然后加入化合物22(40mg,0.007mmol)。反应混合物在室温下搅拌24小时。使用旋转蒸发仪浓缩反应混合物,使用预制的带有PhenomenexC18柱子(洗脱液:A=0.1%TFA溶于水,B=MeCN)的HPLC纯化残余物,得到呈白色固体的化合物35(41mg,22%)。MS(MALDI-TOF)m/z 25963。
实施例11:化合物39(马来酰亚胺-20mPEG-4MMAE)的制备(图12)
化合物37:在0℃下,向胺-PEG20k-CO2H(36)(1.0g,0.05mmol)的无水CH2Cl2(10mL)搅拌溶液中加入DIPEA(83μL,0.5mmol),然后加入6-马来酰亚胺基己酸N-羟基琥珀酰亚胺酯(46mg,0.15mmol)。将混合物在0℃下搅拌1.5小时,然后将溶液从0℃缓慢加热至室温并在氩气下搅拌过夜。除去溶剂,残余物从CH2Cl2/甲基叔丁基醚(2.5mL/20mL)重结晶。分离的固体再次从MeCN/2-丙醇(2mL/30mL)重结晶。残余物在真空下干燥,得到呈白色粉末的化合物37(0.95g,95%)。
化合物38:在氩气、室温下,向化合物37(0.9g,0.045mmol)的无水CH2Cl2(9mL)搅拌溶液中加入DBCO-NH2(37mg,0.14mmol)、EDCI(52mg,0.27mmol)和HOBt(55mg,0.41mmol)。反应混合物在室温下搅拌并通过HPLC监测。除去溶剂,残余物从CH2Cl2/甲基叔丁基醚(2.5mL/20mL)重结晶。分离的固体再次从MeCN/2-丙醇(2mL/30mL)重结晶。将产物在40℃下真空干燥4小时,得到呈白色粉末的产物38(0.86g,89%)。
化合物39:将化合物38(166mg,0.007mmol)溶于无水MeOH(3mL),然后加入化合物22(30mg,0.006mmol)。反应混合物在室温下搅拌24小时。使用旋转蒸发仪除去溶剂,使用预制的带有PhenomenexC18柱子(洗脱液:A=0.1%TFA溶于水,B=MeCN)的HPLC纯化残余物,得到呈白色固体的化合物39(37mg,27%)。HRMS(ESI)或NMR。
实施例12:化合物41(DBCO-20kPEG-4MMAE)的制备(图13)
化合物40:在0℃下,向胺-PEG20k-CO2H(36)(1.0g,0.05mmol)的无水CH2Cl2(10mL)搅拌溶液中加入DIPEA(83μL,0.5mmol),随后加入DBCO-NHS(60mg,0.15mmol)。将混合物在0℃下搅拌1.5小时,然后将溶液从0℃缓慢加热至室温并在氩气下搅拌过夜。除去溶剂,残余物从CH2Cl2/甲基叔丁基醚(2.5mL/20mL)重结晶。分离的固体再次从MeCN/2-丙醇(2mL/30mL)重结晶。残余物在真空下干燥,得到呈白色粉末的化合物40(0.91g,91%)。
化合物41:在氩气下,将化合物40(120mg,0.006mmol)溶解在CH2Cl2/DMF(2mL/2mL)的混合溶剂中,随后加入化合物27(50mg,0.009mmol)、EDCI(6.9mg,0.036mmol)和HOBt(7.3mg,0.054mmol)。反应混合物在室温下搅拌24小时。使用旋转蒸发仪浓缩反应混合物,使用预制的带有PhenomenexC18柱子(洗脱液:A=0.1%TFA溶于水,B=MeCN)的HPLC纯化残余物,得到呈白色固体状的化合物41(53mg,36%)。MS(MALDI-TOF)m/z25450Da。
实施例13:SCAHer2IIxSCAHer2IV(化合物42)的制备(图14)
制备具有SEQ ID NO:1的氨基酸序列的SCAHer2II×SCAHer2IV并如实施例2中所述纯化。具体而言,在离心后收集表达SCAHer2II×SCAHer2IV的宿主细胞培养基的约1.6L上清液,并加载至已用50mM磷酸钠、100mM NaCl、pH 7.0预平衡的Ni-charged柱(2.6cm×13cm)(Cat#AA207311,BestChrome,中国上海)。用50mM磷酸钠、250mM咪唑、100mM NaCl、pH7.0的缓冲液洗脱蛋白质,并在15mL管中分级。获得的82mg捕获蛋白用CaptoL柱(Cat#17-5478-02,GE Healthcare,NJ)进一步纯化。CaptoL柱(1.6cmx8cm)用50mM磷酸钠、100mMNaCl、pH 7.0预平衡,蛋白质用pH 3.0的75mM乙酸洗脱,从而得到58.3mg的蛋白质。图14显示了纯化的化合物42(SCAHer2II×SCAHer2IV)的SDS-PAGE和SEC-HPLC分析。
实施例14:30kmPEG-(SCAHer2IIxSCAHer2IV)-2MMAE(化合物43,JY201)的制备(图15)
在室温下使用还原剂TCEP-HCl的PBS缓冲液(pH=7.4)将蛋白质SCAHer2IIxSCAHer2IV 42处理30分钟,然后用500mM磷酸钠的pH=4.12储液将pH调节至pH6.8。在缀合之前将处理的蛋白质浓缩至5mg/mL。SCAHer2IIxSCAHer2IV与5至10摩尔当量的化合物32(30kmPEG(马来酰亚胺)-2MMAE)的缀合在室温下进行3小时。将反应在室温下用10mM的L-胱氨酸淬灭10分钟。最终产物30kmPEG-(SCAHer2IIxSCAHer2IV)-2MMAE,JY201用阳离子交换色谱柱(CM Fast Flow,Cat#17-0719-01,GE Healthcare,NJ)在pH 6.5的20mM磷酸盐缓冲液中纯化。图15A示意性地说明了制备化合物43的反应方案,所得化合物43通过SDS-PAGE确认(图15B)。
实施例15:SCAHer2IIxSCAHer2IV-20kPEG-4MMAE(化合物44,JY201b)的制备(图16)
在室温下使用还原剂TCEP-HCl的PBS缓冲液(pH=7.4)将蛋白质SCAHer2IIxSCAHer2IV 42处理30分钟,然后用500mM磷酸钠的pH=4.12储液将pH调节至pH6.8。在缀合之前将处理的蛋白质浓缩至5mg/mL。SCAHer2IIxSCAHer2IV与5至10摩尔当量的化合物41(DBCO-20kPEG-4MMAE)的缀合在室温下进行3小时。将反应在室温下用10mM的L-胱氨酸淬灭10分钟。最终产物用尺寸排阻色谱柱HiPrepTM 16/60、SephacrylTM S-300HR(Cat#17-1167-01,GE Healthcare,NJ)在pH 6.5的20mM磷酸盐缓冲液中纯化。图16A示意性地说明了制备化合物44(SCAHer2IIxSCAHer2IV-20kPEG-4MMAE,JY201b)的反应方案,最终化合物44通过SDS-PAGE确认(图16B)。
实施例16:化合物43(JY201)和化合物44(JY201b)的体外细胞毒性(图17,18)
为了评估聚乙二醇化对聚乙二醇化BsADC JY201和JY201b的体外细胞毒性的影响,在将细胞与化合物43(JY201)或化合物44(JY201b)或对照温育后进行细胞活力测定。特别是在平底96孔板中接种4x104个细胞每孔,使细胞粘附。6小时后,用指示剂量的JY201在37℃下处理细胞72小时,然后根据制造商的实验方案在每个孔中加入20μL MTS。然后检测OD490nm处的吸光度,并计算细胞毒性的百分比。
图17显示,JY201对SKBR-3和HCC-827细胞的EC50分别为2.23nM和75.55nM。由于HCC827细胞表达相较于SKBR-3低得多水平的Her2(Kayatani,H.等人,2020,BiochemBiophys Res Commun 532,341-346),这些结果表明,JY201可以诱导具有低Her2表达水平肿瘤细胞的有效细胞毒性。此外,图17左图的结果表明,单链抗体Her2IIxHer2IV对SKBR-3没有诱发可检测的毒性,因此JY201的细胞毒性是由有效载荷MMAE引起的。
使用上述相同的方法,测试JY201对JIMT-1细胞的体外细胞毒性,并与曲妥珠单抗(T-DM1)进行比较。令人惊讶的是,图18A的结果表明,JY201的EC50与T-DM1的EC50非常相似(分别为3.29μg/mL和3.74μg/mL),尽管JY201的DAR(药物到抗体比)仅为2而T-DM1是4。这些结果表明,在诱导肿瘤细胞体外细胞毒性时,仅具有2个有效载荷的聚乙二醇化的BsADCJY201的效力与具有4个有效载荷的T-DM1相当。
进行进一步的实验以测试JY201b的体外细胞毒性(DAR为4),并与JY201和T-DM1进行比较(图18B,C,D和E)。结果表明,具有4个有效载荷的聚乙二醇化的BsADC JY201b比具有2个有效载荷的JY201更有效(图18A和D),并且在指示测试浓度的肿瘤细胞系上比T-DM1相当或更有效。值得注意的是,在测试样品的低端浓度子集中,JY201b在诱导靶标抗原低表达的肿瘤细胞的有效的细胞毒性方面,表现显著优于T-DM1(Her2表达水平:SKBR-3>JIMT-1>ZR75-1,见下表)。这一优点加上更好的毒性特征,为JY201b治疗Her2低表达的癌症患者提供了巨大的希望,而目前的治疗方法对这些患者是无效的。
细胞 | Her2表达 |
SKBR-3 | >3+ |
JIMT-1 | 2+ |
ZR75-1 | 1+ |
实施例17:靶细胞的JY201内化(图19)
为了研究实施例16中所示的细胞毒性效果的机制,通过Matsuzaki(Matsuzaki,S.等人,2018,International Journal of Cancer 142,1056-1066)所述的流式细胞术方法,检查SKBR-3细胞对聚乙二醇化BsADC JY201的内化。在胰蛋白酶化后,通过含有2%FBS的PBS洗涤SKBR-3细胞并以1×107/mL的浓度重悬。细胞悬液以100μL/管等分。将SKBR-3细胞用10μg/mL Flour647标记的T-DM1或JY2014℃下过夜处理。用预冷的PBS洗涤两次后,将细胞在37℃下培养指示的时间段,以使T-DM1和JY201内化。将孵育的细胞用3×200μL FACS缓冲液洗涤。在最终洗涤之后,加入100Ml FACS缓冲液以重悬细胞进行流式细胞术分析。使用如下公式计算内化速率:
(4℃下的总MFI-37℃下的总MFI)/4℃下的总MFI×100%。
图19的结果表明,在测试的所有时间点,SKBR-3细胞的JY201的内化速率约是T-DM1的两倍,尽管JY201对靶标的亲和力比T-DM1要弱得多(数据未显示)。该结果意味着传统Fc承载的ADC采用的动态内化和流出机制可能不适用于本发明公开的聚乙二醇化ADC。值得注意的是,与传统ADC的Fc组分例如正常组织或细胞上的FcγR或甘露糖受体的结合相关的内化机制通常导致脱靶毒性,甚至是ADC药物的剂量限制性毒性(Krop IE,等人,J ClinOncol,30,3234-41,2012;Uppal,H.等人,2015,Clin Cancer Res 21,123-133;Gorovits,B.等人,2013,Cancer Immunol Immunother 62,217-223)。
实施例18:JY201内化后未流出靶细胞(图20)
Fc承载的ADC在内化之后,常见流出靶细胞。这可能导致脱靶毒性,降低有效性和耐药性。这种现象已经归因于FcRn介导的再循环(Junghans,R.P.等人,1996,Proc NatlAcad Sci U S A 93,5512-5516;Ryman,J.T.等人,2017,CPT Pharmacometrics SystPharmacol 6,576-588)。据报道,50%内化曲妥单抗在内化5分钟内流出靶细胞,这一数字在内化30分钟内增加到85%(Barok,M.,Joensuu等人,2014,Breast Cancer Res 16,209-209)。
为了检查JY201在内化后是否流出靶细胞,遵循制造商提供的实验方案将HRP(辣根过氧化物酶)与JY201缀合。在平底96孔板中接种3x104个SK-BR3细胞过夜,使细胞粘附。第二天,洗涤细胞并与0.25μg/mL的JY201在室温下孵育18小时。用完全培养基洗涤3次后,将细胞进一步在37℃下孵育。在不同时间点收集细胞裂解物和上清液。通过加入50μL/孔TMB(3,3′,5,5′-四甲基联苯胺)溶液检测细胞裂解液和细胞上清液中JY201-HRP的含量。以50μL/孔0.2M硫酸终止反应后,在微孔板分析仪上测得OD450。对T-DM1进行了相同的实验,将0.25μg/mL T-DM1-HRP与细胞一起孵育4小时,然后洗涤、更换培养基并进一步孵育2小时和24小时。
图20A显示,与0小时相比,上清液进一步孵育3小时和6小时,其中的JY201并未显著增加。同时,细胞裂解物内的JY201在3小时和6小时也没有减少(图20B)。此外,0小时时细胞裂解物的OD450比上清液的OD450高至少2倍。可以看出JY201被内化并且内化的JY201没有流出到上清液中。
为了比较,还测量了上清液中T-DM1的水平,其在孵育2小时后显著增加(p<0.001)(图20C)。此外,培养24小时后T-DM1的水平显著高于培养2小时,表明T-DM1的持续流出。一致地,细胞裂解物中的T-DM1在24小时时显著降低(p<0.001)(图20D)。T-DM1的流出机制可能导致药物临床疗效的降低和毒性的增加。
总体而言,来自图20的数据表明了JY201没有再循环或流出机制的出人意料的结果,这可能是由于JY201缺少Fc组分。
实施例19:JY201对巨核细胞无细胞毒性(图21)
以低血小板计数为特征的血小板减少症是接受ADC治疗的癌症患者的主要不良事件(Uppal,H.等人,2015,Clin Cancer Res 21,123-133;Donaghy,H.2016,MAbs 8,659-671;de Goeij,BE等人,2016,Curr Opin Immunol 40,14-23),这导致了T-DM1的剂量限制性毒性(Krop IE,等人,J Clin Oncol,30,3234-41,2012)。为检验JY201与血小板减少症相关的细胞毒性,测试了JY102对DAMI(是终末分化血小板的母细胞的巨核细胞细胞系(Lev,P.R.等人,2011,Platelets 22,28-38))的结合和细胞毒性。
在结合实验中,收集DAMI细胞并在含有2%FBS的冰预冷PBS中重悬至约5x106个细胞/mL的浓度。然后将细胞与JY201或对照一起孵育,并使用实施例17中描述的相同方法进行流式细胞术分析。使用实施例16中描述的相同方法评估对DAMI细胞的体外细胞毒性。
图21C中显示的结果表明,即使在50μg/mL的高浓度下,聚乙二醇化的BsADC JY201令人惊讶地没有对DAMI细胞引发细胞毒性,而T-DM1在测试浓度下引发了显著的药物特异性细胞毒性。这出人意料的结果与图21A和21B中的结果一致,其中FITC标记的T-DM1与DAMI细胞结合,而JY201不与之结合,可能是因为其缺乏Fc区。
总之,目前的数据表明JY201的细胞毒性是组织特异性的,其仅对肿瘤细胞而不对巨核细胞发挥细胞毒性。JY201出人意料的优越特性为解决由ADC诱导的血小板减少症和其他病症引起的临床上的一些主要不良事件提供了很好的机会。
优选实施方案的前述示例和描述应当被视为说明,而不是限制由权利要求限定的本发明。应当容易理解,在不脱离如权利要求中阐述的本发明的情况下,可以利用上述特征的多种变化和组合。此类变化不应视为脱离本发明的范围,并且所有此类变化均意在包括在所附权利要求的范围内。
序列表
<110> 深圳康源久远生物技术有限公司
<120> 抗体药物缀合物
<130> F21W8688
<150> PCT/CN2020/084880
<151> 2020-04-15
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Claims (52)
1.式(Ib)的化合物
其中:
P是非免疫原性聚合物;
M是H或选自C1-50烷基和芳基的封端基团,其中所述烷基的一个或多个碳任选地被杂原子取代;
y是选自1至10的整数;
A是抗体或其抗原结合片段,以及
T是多官能小分子接头部分;
L1和L2各自独立地是异型或同型双官能接头;
a和b各自是选自0至10的整数;
B是带支链接头,其中每个支链具有与自消解间隔物连接的氨基酸序列或碳水化合物部分,其中所述氨基酸序列或碳水化合物部分通过酶的裂解触发自消解机制以释放D,或每个支链具有二硫键或可裂解键,其中所述二硫键或可裂解键的裂解释放D或其衍生物;
D各自独立地是细胞毒性小分子或肽;以及
n是选自1至25的整数。
2.权利要求1的化合物,其中T是衍生自具有三个官能团的分子的三官能接头,所述官能团独立地选自羟基、氨基、肼基、叠氮化物、烯烃、炔烃、羧基(醛、酮、酯、羧酸、酸酐、酰基卤化物)、硫醇、二硫化物、腈、环氧化物、亚胺、硝基和卤化物,并且其中T和(L1)a之间的连接以及T和(L2)b之间的连接相同或不同。
3.权利要求2的化合物,其中T是赖氨酸或衍生自赖氨酸。
4.权利要求1至3中任一项的化合物,其中所述L1接头末端的官能团能够与A位点特异性缀合,并且选自硫醇、马来酰亚胺、2-吡啶基二硫代变体、芳族砜或乙烯基砜、丙烯酸酯、溴代或碘代乙酰胺、叠氮化物、炔烃、二苯并环辛基(DBCO)、羰基、2-氨基-苯甲醛或2-氨基-苯乙酮基团、酰肼、肟、酰基三氟硼酸钾、O-氨基甲酰基羟基胺、反式环辛烯、四嗪、三芳基膦、硼酸和碘。
5.权利要求1至4中任一项的化合物,其中所述抗体是单特异性或多特异性全长抗体、单链抗体、纳米抗体或其抗原结合结构域。
6.权利要求1至5中任一项的化合物,其中所述抗体是单特异性单链抗体。
7.权利要求6的化合物,其中所述单特异性单链抗体与肿瘤相关抗原(TAA)如Her2结合。
8.权利要求7的化合物,其中所述单特异性单链抗体具有两个与Her2结合的结合结构域。
9.权利要求8的化合物,其中所述单特异性单链抗体具有如SEQ ID NO:2所示的氨基酸序列。
10.权利要求1至5中任一项的化合物,其中所述抗体是双特异性抗体,例如双特异性单链抗体。
11.权利要求10的化合物,其中所述双特异性抗体的两个结合结构域与相同的肿瘤相关抗原(TAA)结合、与两个不同的TAA结合、或与TAA以及T细胞(例如T细胞受体的组分)或NK细胞上表达的抗原结合。
12.权利要求11的化合物,其中所述抗体是抗Her2 x抗Her2单链双特异性抗体。
13.权利要求12的化合物,其中所述抗体具有如SEQ ID NO:1所示的氨基酸序列。
14.权利要求6至9中任一项的化合物,其中所述单特异性单链抗体的两个结合结构域通过接头连接,并且其中所述接头包含半胱氨酸或非天然氨基酸残基用于所述抗体与L1的位点特异性缀合。
15.权利要求10至13中任一项的化合物,其中所述双特异性单链抗体的两个结合结构域通过接头连接,并且其中所述接头包含半胱氨酸或非天然氨基酸残基用于所述抗体与L1的位点特异性缀合。
16.权利要求14至15中任一项的化合物,其中所述非天然氨基酸选自基因编码的烯烃赖氨酸(如N6-(己-5-烯酰基)-L-赖氨酸)、2-氨基-8-氧代壬酸、间或对-乙酰苯丙氨酸、含有β-二酮侧链的氨基酸(如2-氨基-3-(4-(3-氧代丁酰基)苯基)丙酸)、(S)-2-氨基-6-(((1R,2R)-2-叠氮环戊氧基)羰基氨基)己酸、叠氮高丙氨酸、吡咯赖氨酸类似物N6-((丙-2-炔-1-氧基)羰基)-L-赖氨酸、(S)-2-氨基-6-戊-4-氨基己酸、(S)-2-氨基-6-((丙-2-炔氧基)羰基氨基)己酸、(S)-2-氨基-6-((2-叠氮乙氧基)羰基氨基)己酸、p-叠氮苯丙氨酸、对叠氮苯丙氨酸、Nε-丙烯酰-1-赖氨酸、Nε-5-降冰片烯-2-氧基羰基-1-赖氨酸、N-ε-(环辛-2-炔-1-氧基)羰基)-L-赖氨酸、N-ε-(2-(环辛-2-炔-1-氧基)乙基)羰基-L-赖氨酸、基因编码的四嗪氨基酸(如4-(6-甲基-s-四嗪-3-基)氨基苯丙氨酸)。
17.权利要求1至16中任一项的化合物,其中D选自DNA交联剂、微管抑制剂、DNA烷化剂、拓扑异构酶抑制剂或其组合。
18.权利要求17的化合物,其中D选自MMAE、MMAF、SN38、DM1、DM4、刺孢毒素、吡咯并苯二氮卓类、倍癌霉素或其衍生物、或其组合。
19.权利要求17的化合物,其中D选自长春花生物碱、laulimalide、紫杉烷、秋水仙碱、微管溶素(tubulysin)、念珠藻素(Cryptophycin)、哈米特林(Hemiasterlin)、西马多丁(Cemadotin)、根霉素(Rhizoxin)、圆皮海绵内酯(Discodermolide)、根薯酮内酯(taccalonolide)A或B或AF或AJ、根薯酮内酯AI-环氧化物、CA-4、埃博霉素A和B、laulimalide、紫杉醇、多西他赛、阿霉素、喜树碱、iSGD-1882、centanamycin、PNU-159682、uncialamycin、吲哚并苯二氮卓二聚体、β-鹅膏蕈碱、毒伞毒素(Amatoxin)、泰兰斯他汀类(thailanstatin)或其衍生物或类似物,或其组合。
20.权利要求1至19中任一项的化合物,其中所述非免疫原性聚合物是聚乙二醇(PEG)。
21.权利要求20的化合物,其中所述PEG是直链PEG或带支链的PEG。
22.权利要求20至21中任一项的化合物,其中所述聚乙二醇的至少一个末端用甲基或低分子量烷基封端。
23.权利要求20至22中任一项的化合物,其中所述PEG的总分子量为100至80000。
24.权利要求20至23中任一项的化合物,其中所述PEG通过永久键或可裂解键与三官能或四官能或任何其他环状或非环状或非环状多官能部分T(例如赖氨酸)连接。
26.权利要求25的化合物,其中L1的接头末端的官能团能够与A位点特异性缀合,并且选自硫醇、马来酰亚胺、2-吡啶基二硫代变体、芳族砜或乙烯基砜、丙烯酸酯、溴代或碘代乙酰胺、叠氮化物、炔烃、二苯并环辛基(DBCO)、羰基、2-氨基-苯甲醛或2-氨基-苯乙酮基团、酰肼、肟、酰基三氟硼酸钾、O-氨基甲酰基羟基胺、反式环辛烯、四嗪、三芳基膦、硼酸和碘。
27.权利要求25至26中任一项的化合物,其中所述抗体是单特异性或多特异性全长抗体、单链抗体、纳米抗体或其抗原结合结构域。
28.权利要求27的化合物,其中所述抗体是单特异性单链抗体,任选地,其中所述单特异性单链抗体与肿瘤相关抗原(TAA)如Her2结合。
29.权利要求28的化合物,其中所述单特异性单链抗体具有两个与Her2结合的结合结构域。
30.权利要求29的化合物,其中所述单特异性单链抗体具有如SEQ ID NO:2所示的氨基酸序列。
31.权利要求27的化合物,其中所述抗体是双特异性抗体,例如双特异性单链抗体。
32.权利要求31的化合物,其中所述双特异性抗体的两个结合结构域与相同的肿瘤相关抗原(TAA)结合、与两个不同的TAA结合、或与TAA以及T细胞(例如T细胞受体的组分)或NK细胞上表达的抗原结合。
33.权利要求32的化合物,其中所述抗体是抗Her2 x抗Her2单链双特异性抗体。
34.权利要求33的化合物,其中所述抗体具有如SEQ ID NO:1所示的氨基酸序列。
35.权利要求28至30中任一项的化合物,其中所述单特异性单链抗体的两个结合结构域通过接头连接,并且其中所述接头包含半胱氨酸或非天然氨基酸残基用于所述抗体与L1的位点特异性缀合。
36.权利要求31至34中任一项的化合物,其中所述双特异性单链抗体的两个结合结构域通过接头连接,并且其中所述接头包含半胱氨酸或非天然氨基酸残基用于所述抗体与L1的位点特异性缀合。
37.权利要求35至36中任一项的化合物,其中用于所述抗体与L1的位点特异性缀合的所述非天然氨基酸残基选自基因编码的烯烃赖氨酸(如N6-(己-5-烯酰基)-L-赖氨酸)、2-氨基-8-氧代壬酸、间或对-乙酰苯丙氨酸、含有β-二酮侧链的氨基酸(如2-氨基-3-(4-(3-氧代丁酰基)苯基)丙酸)、(S)-2-氨基-6-(((1R,2R)-2-叠氮环戊氧基)羰基氨基)己酸、叠氮高丙氨酸、吡咯赖氨酸类似物N6-((丙-2-炔-1-氧基)羰基)-L-赖氨酸、(S)-2-氨基-6-戊-4-氨基己酸、(S)-2-氨基-6-((丙-2-炔氧基)羰基氨基)己酸、(S)-2-氨基-6-((2-叠氮乙氧基)羰基氨基)己酸、p-叠氮苯丙氨酸、对叠氮苯丙氨酸、Nε-丙烯酰-1-赖氨酸、Nε-5-降冰片烯-2-氧基羰基-1-赖氨酸、N-ε-(环辛-2-炔-1-氧基)羰基)-L-赖氨酸、N-ε-(2-(环辛-2-炔-1-氧基)乙基)羰基-L-赖氨酸、基因编码的四嗪氨基酸(如4-(6-甲基-s-四嗪-3-基)氨基苯丙氨酸)。
38.权利要求25至37中任一项的化合物,其中D选自DNA交联剂、微管抑制剂、DNA烷化剂、拓扑异构酶抑制剂或其组合。
39.权利要求38的化合物,其中D选自MMAE、MMAF、SN38、DM1、DM4、刺孢毒素、吡咯并苯二氮卓类、倍癌霉素或其衍生物、或其组合。
40.权利要求38的化合物,其中D选自长春花生物碱、laulimalide、紫杉烷、秋水仙碱、微管溶素(tubulysin)、念珠藻素(Cryptophycin)、哈米特林(Hemiasterlin)、西马多丁(Cemadotin)、根霉素(Rhizoxin)、圆皮海绵内酯(Discodermolide)、根薯酮内酯(taccalonolide)A或B或AF或AJ、根薯酮内酯AI-环氧化物、CA-4、埃博霉素A和B、laulimalide、紫杉醇、多西他赛、阿霉素、喜树碱、iSGD-1882、centanamycin、PNU-159682、uncialamycin、吲哚并苯二氮卓二聚体、β-鹅膏蕈碱、毒伞毒素(Amatoxin)、泰兰斯他汀类(thailanstatin)或其衍生物或类似物,或其组合。
41.权利要求25至40中任一项的化合物,其中所述PEG的总分子量为100至80000。
42.权利要求1至41中任一项的化合物,其中L1和L2各自独立地选自:
-(CH2)aXY(CH2)b-,
-X(CH2)aO(CH2CH2O)c(CH2)bY-,
-(CH2)a杂环基-,
-(CH2)aX-,
-X(CH2)aY-,
-W1-(CH2)aC(O)NR1(CH2)bO(CH2CH2O)c(CH2)dC(O)-,
-C(O)(CH2)aO(CH2CH2O)b(CH2)cW2C(O)(CH2)dNR1-,
-W3-(CH2)aC(O)NR1(CH2)bO(CH2CH2O)c(CH2)dW2C(O)(CH2)eC(O)-,
其中a、b、c、d和e各自独立地为选自0至25的整数;X和Y各自独立地选自C(=O)、NR1、S、O、CR2R3或无;R1和R2独立地代表氢、C1-10烷基或(CH2)1-10C(=O);W1和/或W3衍生自基于马来酰亚胺基的部分,且W2代表含三唑基或四唑基的基团;杂环基选自马来酰亚胺基衍生的部分或基于四唑基或基于三唑基的部分。
44.权利要求1至43中任一项的化合物,其中所述带支链接头B包含延伸间隔物、触发单元、自消解间隔物或其任何组合,任选地,其中所述触发单元是可由酶裂解的氨基酸序列或β-葡萄糖苷酸(β-glucoronide)或β-半乳糖苷触发部分,所述酶例如为组织蛋白酶B、纤溶酶、基质金属蛋白酶(MMP)、β-葡萄糖醛酸酶、β-半乳糖苷酶;可在酸性pH条件下释放药物D或其衍生物的pH敏感接头;或可通过谷胱甘肽、硫氧还蛋白家族成员(WCGH/PCK)或硫还原酶释放药物D或其衍生物的二硫键接头。
45.权利要求44的化合物,其中所述带支链接头B选自
其中:
a、b、c、d、e和f各自为整数,并且独立地选自1至25;
(A)n是氨基酸序列触发单元,例如Val-Cit、al-Ala、Val-Lys、Phe-Lys、Phe-Cit、Phe-Arg、Phe-Ala、Ala-Lys、Leu-Cit、Ile-Cit、Trp-Cit、D-Phe-LPhe-Lys、Phe-Phe-Lys、D-Phe-Phe-Lys、Gly-Phe-Lys、Gly-Phe-Leu-Gly、或Ala-Leu-Ala-Leu;
PAB是对氨基苄醇;
Ex各自是包含接头链的延伸间隔物,其独立地选自:
-NR1(CH2)xO(CH2CH2O)y(CH2)zC(O)-,
-C(O)(CH2)xNR1-,
-NR1(CH2)xO(CH2CH2O)y(CH2)zNR2-,
-NR1(CH2)xNR2-,
-NR1(CH2)xO(CH2CH2O)y(CH2)zO-,
-O(CH2)xNR1-,
-C(O)(CH2)xO-,
-O(CH2)xO(CH2CH2O)y(CH2)zC(O)-,
-C(O)(CH2)xO(CH2CH2O)y(CH2)zC(O)-,
-C(O)(CH2)xC(O)-,
或无,
其中x、y和z各自是整数,并且独立地选自0至25;R1和R2独立地代表氢或C1-10烷基。
49.制备权利要求1至48中任一项的化合物的方法,其包括:
a)制备经非免疫原性修饰的(例如聚乙二醇化的)药物缀合物的步骤,所述药物缀合物具有用于位点特异性缀合的游离官能团;
b)将所述非免疫原性修饰(例如聚乙二醇化的)药物缀合物与抗体进行位点特异性缀合以提供式(Ib)或(Ic)的化合物的步骤。
50.药物制剂,其包含有效量的权利要求1至48中任一项的化合物和药学上可接受的盐、载体或赋形剂。
51.权利要求1至48中任一项的化合物,其用于治疗癌症,所述癌症选自乳腺癌、卵巢癌、前列腺癌、肺癌、胰腺癌、肾癌、膀胱癌、胃癌、结肠癌、结直肠癌、唾液腺癌、甲状腺癌和子宫内膜癌。
52.权利要求1至48中任一项的化合物,其与有效量的另一种抗癌剂、免疫抑制剂组合用于治疗癌症,所述癌症选自乳腺癌、卵巢癌、前列腺癌、肺癌、胰腺癌、肾癌、膀胱癌、胃癌、结肠癌、结直肠癌、唾液腺癌、甲状腺癌和子宫内膜癌。
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WO2024022384A1 (en) * | 2022-07-28 | 2024-02-01 | Shenzhen Enduring Biotech , Ltd. | Peg based anti-cd47/anit-pd-l1 bispecific antibody-drug conjugate |
CN115429890A (zh) * | 2022-08-04 | 2022-12-06 | 辽宁键凯科技有限公司 | 一种缀合物及用其制备的抗体药物偶联物 |
CN115429890B (zh) * | 2022-08-04 | 2024-05-24 | 辽宁键凯科技有限公司 | 一种缀合物及用其制备的抗体药物偶联物 |
CN117343125A (zh) * | 2023-12-06 | 2024-01-05 | 瑞博(苏州)制药有限公司 | 一种抗体偶联药物连接子的合成方法 |
CN117343125B (zh) * | 2023-12-06 | 2024-04-16 | 瑞博(苏州)制药有限公司 | 一种抗体偶联药物连接子的合成方法 |
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WO2021209007A1 (en) | 2021-10-21 |
AU2021256223A1 (en) | 2022-11-10 |
BR112022020124A2 (pt) | 2022-11-29 |
US20230104728A1 (en) | 2023-04-06 |
EP4117729A4 (en) | 2023-11-15 |
JP2023521920A (ja) | 2023-05-25 |
EP4117729A1 (en) | 2023-01-18 |
AU2021256223B2 (en) | 2024-04-18 |
MX2022013000A (es) | 2022-11-08 |
CA3174407A1 (en) | 2021-10-21 |
KR20230002672A (ko) | 2023-01-05 |
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