CN110507824A - 一种抗间皮素抗体及其抗体药物缀合物 - Google Patents
一种抗间皮素抗体及其抗体药物缀合物 Download PDFInfo
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- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
Abstract
本发明公开了一种靶向于MSLN的抗体药物缀合物。本发明还公开了制备所述抗体药物缀合物(ADC)的方法。本发明还公开了一种新型的MSLN抗体或其功能性片段,其包含经改造的重链和轻链。
Description
技术领域
本发明涉及一种抗间皮素抗体或其功能性片段。本发明还涉及包含抗间皮素抗体和小分子药物的抗体药物缀合物。本发明还涉及本发明的抗体和缀合物在制备用于治疗肿瘤的药物中的用途。
背景技术
MSLN(间皮素、Mesothelin)是由单克隆抗体CAK1在间皮细胞、间皮瘤和卵巢癌中识别的抗原,是一种分子为40kDa的细胞表面糖蛋白,其高表达于多种肿瘤组织中,为一个非常好的治疗型抗体的靶向标志物。
虽然单克隆抗体治疗靶点特异性高,副作用低,但是单独使用时疗效比较有限。抗体药物缀合物是将毒素通过连接子与抗体相连,其同时具有较强的靶向性和高效的细胞毒性两大特点,使得ADC新药成为最有前景的免疫治疗方法之一,在癌症免疫治疗中备受关注。
已有一些研究小组构建了靶向MSLN的抗体药物缀合物,但是这些抗体药物缀合物仍然存在着诸多缺点,例如:通过抗体上半胱氨酸的巯基进行偶联会导致抗体的肽链之间原本的二硫键丧失,得到的ADC不稳定,一旦进入循环,ADC的半衰期会缩短,毒副作用较大;利用抗体上赖氨酸的氨基进行偶联使得偶联位点随机,影响抗体的靶向性。
因此,本领域中仍然需要开发具有更加优越性质的MSLN抗体以及包含该抗体的抗体药物缀合物。
发明内容
本发明提供了一种抗间皮素抗体或其功能性片段,以及包含该抗体或其功能性片段的抗体药物缀合物。特别地,本发明的抗体药物缀合物具有更高的稳定性和更低的毒副作用,和/或对间皮素具有更高的亲和力。
具体的:
一方面,本发明提供了一种抗体药物缀合物,其中所述抗体药物缀合物的结构通式为:
Ab-(L-D)n
其中:
所述Ab为特异性结合MSLN的抗体或其功能性片段;
所述L为空或任一连接子;
所述D为任一治疗剂;
n为选自1到8的整数,例如1、2、3、4、5、6、7或8或其任意两者的区间。
进一步的,本发明的抗体或其功能性片段包含重链和轻链,其中(i)所述重链包含至少三个CDR区,其中所述CDR区中至少一个的氨基酸序列具有如SEQ ID NO:1、2或3所示的氨基酸序列或者与其具有至少80%(优选85%、90%、95%、98%或者99%)序列同一性的序列;并且(ii)所述轻链包含至少三个CDR区,其中所述CDR区中至少一个的氨基酸序列具有如SEQ ID NO:4、5或6所示的氨基酸序列或者与其具有至少80%(优选85%、90%、95%、98%或者99%)序列同一性的序列。优选的,本发明的抗体或其功能性片段包含重链和轻链,其中(i)所述重链可变区包含三个CDR区,其中所述CDR区分别具有如SEQ ID NO:1、2或3所示的氨基酸序列;和/或(ii)所述轻链可变区包含三个CDR区,其中所述CDR区分别具有如SEQ ID NO:4、5或6所示的氨基酸序列。最优选的,本发明公开的抗间皮素抗体重链的CDR的氨基酸序列分别如SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3所示,其轻链可变区的CDR的氨基酸序列分别如SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6所示。
更进一步的,本发明提供了一种抗间皮素抗体或其功能性片段,其包括重链可变区和轻链可变区,其中(i)所述重链可变区包含SEQ ID NO:7所示的氨基酸序列或者与其具有至少80%(优选85%、90%、95%、98%或者99%)序列同一性的序列;并且(ii)所述轻链可变区包含SEQ ID NO:8所示的氨基酸序列或者与其具有至少80%(优选85%、90%、95%、98%或者99%)序列同一性的序列。优选的,所述抗体包含重链和轻链,其中(i)所述重链可变区包含SEQ ID NO:7所示的氨基酸序列,和/或(ii)所述轻链可变区包含SEQ ID NO:8所示的氨基酸序列。最优选的本发明公开的抗间皮素抗体重链可变区包含SEQ ID NO:7所示的氨基酸序列,所述轻链可变区包含SEQ ID NO:8所示的氨基酸序列。
在某些具体实施方案中,本发明的抗体包含重链和轻链,其中所述重链包含SEQID NO:10所示的氨基酸序列,所述轻链包含SEQ ID NO:9所示的氨基酸序列。
另一方面,本发明提供了抗体药物缀合物,其包含抗间皮素抗体或其功能性片段以及治疗剂。优选地,本发明的抗体药物缀合物还包含连接子,其将所述抗间皮素抗体或其功能性片段与治疗剂相连。
在某些实施方案中,本发明的连接子L可通过本领域已知的任何方式与抗体连接,优选地通过巯基和/或氨基连接。在一个优选的方案中,本发明的抗体通过抗体上的巯基与连接子连接。本发明中的连接子L可以不存在(即抗体与治疗剂D直接相连)或者任一可裂解(即可在体内环境下发生断裂的接头)或者不可裂解的连接子或者其组合,优选的,所述连接子可以选自下表1中所列出的那些。
表1本发明的抗体缀合物中可用的连接子
在一些实施方案中,本发明的连接子优选的选自下表2中所列出的那些连接子。
表2本发明的抗体缀合物中可用的优选连接子
在本发明的一些实施方案中,所述治疗剂D选自:美坦生类化合物、V-ATP酶抑制剂、促凋亡剂、Be 12抑制剂、McL1抑制剂、HSP90抑制剂、IAP抑制剂、mTOr抑制剂、微管稳定剂、微管去稳定剂、阿里他汀(auristatin)、多拉司他汀(dolastatin)、MetAP(甲硫氨酸氨肽酶)、蛋白质CRMl的核输出抑制剂、DPPIV抑制剂、蛋白酶体抑制剂、线粒体中磷酰基转移反应的抑制剂、蛋白质合成抑制剂、激酶抑制剂、CDK2抑制剂、CDK9抑制剂、驱动蛋白抑制剂、HDAC抑制剂、DNA损伤剂、DNA烷基化剂、DNA嵌入剂、DNA小沟结合剂、DHFR抑制剂、以及海兔毒素肽。
在本发明的一些优选实施方案中,所述治疗剂D为细胞毒类物质(例如抗代谢药、抗肿瘤抗生素、生物碱)、免疫增强剂或放射性同位素。优选地,所述治疗剂D可选自MMAD(单甲基澳瑞他汀D,Monomethyl auristatin D)及其衍生物、MMAE(单甲基澳瑞他汀E,Monomethyl auristatin E)及其衍生物、MMAF(单甲基澳瑞他汀F,Monomethyl auristatinF)及其衍生物、美登素类衍生物DM1(Mertansine derivative M1)、美登素类衍生物DM4(Mertansine derivative M4)、Duocarmycine、Calicheamicin、PBDA(Pyrrolobenzodiazepines)、Doxorubicin、Vinca Alkaloids、Metrotrexate、Vinblastine、Daunorubicin,更优选地所述治疗剂选自美登素类(maytansinoids)(例如安丝菌素(Ansamitocin)或者美登素(Mertansine))、海兔毒素肽(dolastatin)及其衍生物,最优选地所述治疗剂选自MMAD和MMAE。
在某些具体实施方案中,本发明涉及结构通式为Ab-(L-D)n的抗体药物缀合物,Ab为本发明所述的任一抗间皮素抗体,L选自Py-MAA-Val-Cit-PAB、Mc-Val-Cit-PAB,D选自MMAD或MMAE,以及n为选自1到8的整数,例如1、2、3、4、5、6、7、8或其任意两者的区间。
在某些具体实施方案中,本发明的抗体药物缀合物具有如下式任一所示的结构:
其中n为1、2、3、4、5、6、7或8。
特别地,本发明涉及结构通式为Ab-(L-D)n的抗体药物缀合物,其中Ab为本发明所述的任一抗间皮素抗体,所述抗体的重链可变区的CDR氨基酸序列分别如SEQ ID NO:1、SEQID NO:2、SEQ ID NO:3所示,所述抗体的轻链可变区的CDR氨基酸序列分别如SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6所示;L为Py-MAA-Val-Cit-PAB,D为MMAE。更特别地,本发明的抗体药物缀合物为RC88-Py-MAA-Val-Cit-PAB-MMAE,其具有下式所示的结构,其中n为1、2、3、4、5、6、7或8:
特别地,本发明涉及结构通式为Ab-(L-D)n的抗体药物缀合物,其中Ab为本发明所述的任一抗间皮素抗体,所述抗体的重链可变区的CDR的氨基酸序列分别如SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3所示,所述抗体的轻链可变区的CDR的氨基酸序列分别如SEQ IDNO:4、SEQ ID NO:5、SEQ ID NO:6所示;L为Py-MAA-Val-Cit-PAB,D为MMAD。更特别地,本发明的抗体药物缀合物为RC88-Py-MAA-Val-Cit-PAB-MMAD,其具有下式所示的结构,其中n为1、2、3、4、5、6、7或8:
特别地,本发明涉及结构通式为Ab-(L-D)n的抗体药物缀合物,其中Ab为本发明所述的任一抗间皮素抗体,所述抗体的重链可变区的CDR的氨基酸序列分别如SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3所示,所述抗体的轻链可变区的CDR的氨基酸序列分别如SEQ IDNO:4、SEQ ID NO:5、SEQ ID NO:6所示;L为Mc-Val-Cit-PAB,D为MMAE。更特别地,本发明的抗体药物缀合物为RC88-Mc-Val-Cit-PAB-MMAE,其具有下式所示的结构,其中n为1、2、3、4、5、6、7或8:
特别地,本发明涉及结构通式为Ab-(L-D)n的抗体药物缀合物,其中Ab为本发明所述的任一抗间皮素抗体,所述抗体的重链可变区的CDR的氨基酸序列分别如SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3所示,所述抗体的轻链可变区的CDR的氨基酸序列分别如SEQ IDNO:4、SEQ ID NO:5、SEQ ID NO:6所示;L为Mc-Val-Cit-PAB,D为MMAD。更特别地,本发明的抗体药物缀合物为RC88-Mc-Val-Cit-PAB-MMAD,其具有下式所示的结构,其中n为1、2、3、4、5、6、7或8:
特别地,本发明涉及结构通式为Ab-(L-D)n的抗体药物缀合物,其中Ab为本发明所述的任一抗间皮素抗体,所述抗体具有SEQ ID NO:7所示的重链可变区序列和SEQ ID NO:8所示的轻链可变区序列;L为Py-MAA-Val-Cit-PAB,D为MMAE。更特别地,本发明的抗体药物缀合物为RC88-Py-MAA-Val-Cit-PAB-MMAE,其具有下式所示的结构,其中n为1、2、3、4、5、6、7或8:
特别地,本发明涉及结构通式为Ab-(L-D)n的抗体药物缀合物,其中Ab为本发明所述的任一抗间皮素抗体,所述抗体具有SEQ ID NO:7所示的重链可变区序列和SEQ ID NO:8所示的轻链可变区序列;L为Py-MAA-Val-Cit-PAB,D为MMAD。更特别地,本发明的抗体药物缀合物为RC88-Py-MAA-Val-Cit-PAB-MMAD,其具有下式所示的结构,其中n为1、2、3、4、5、6、7或8:
特别地,本发明涉及结构通式为Ab-(L-D)n的抗体药物缀合物,其中Ab为本发明所述的任一抗间皮素抗体,所述抗体具有SEQ ID NO:7所示的重链可变区序列和SEQ ID NO:8所示的轻链可变区序列;L为Mc-Val-Cit-PAB,D为MMAE。更特别地,本发明的抗体药物缀合物为RC88-Mc-Val-Cit-PAB-MMAE,其具有下式所示的结构,其中n为1、2、3、4、5、6、7或8:
特别地,本发明涉及结构通式为Ab-(L-D)n的抗体药物缀合物,其中Ab为本发明所述的任一抗间皮素抗体,所述抗体的具有SEQ ID NO:7所示的重链可变区序列和SEQ IDNO:8所示的轻链可变区序列;L为Mc-Val-Cit-PAB,D为MMAD。更特别地,本发明的抗体药物缀合物为RC88-Mc-Val-Cit-PAB-MMAD,其具有下式所示的结构,其中n为1、2、3、4、5、6、7或8:
另一方面,本发明提供了一种能够结合间皮素的抗体或其功能性片段,所述的抗体或其功能性片段包含重链和轻链,其中
(i)所述重链包含至少三个CDR区,其中所述CDR区中至少一个的氨基酸序列具有如SEQ ID NO:1、2或3所示的氨基酸序列或者与其具有至少80%(优选85%、90%、95%、98%或者99%)序列同一性的序列;和/或
(ii)所述轻链包含至少三个CDR区,其中所述CDR区中至少一个的氨基酸序列具有如SEQ ID NO:4、5或6所示的氨基酸序列或者与其具有至少80%(优选85%、90%、95%、98%或者99%)序列同一性的序列。
在某些具体的实施方案中,本发明的抗间皮素抗体或其功能性片段包含重链和轻链,其中:
(i)所述重链可变区包含三个CDR区,其中所述CDR区分别具有如SEQ ID NO:1、2或3所示的氨基酸序列;和/或
(ii)所述轻链可变区包含三个CDR区,其中所述CDR区分别具有如SEQ ID NO:4、5或6所示的氨基酸序列。
特别地,本发明公开的抗间皮素抗体重链的CDR区的氨基酸序列分别如SEQ IDNO:1、SEQ ID NO:2、SEQ ID NO:3所示。
特别地,本发明公开的抗间皮素抗体轻链的CDR区的氨基酸序列分别如SEQ IDNO:4、SEQ ID NO:5、SEQ ID NO:6所示。
更特别地,本发明公开的抗间皮素抗体重链的CDR区的氨基酸序列分别如SEQ IDNO:1、SEQ ID NO:2、SEQ ID NO:3所示,其轻链可变区的CDR区的氨基酸序列分别如SEQ IDNO:4、SEQ ID NO:5、SEQ ID NO:6所示。
又一方面,本发明提供了一种抗间皮素抗体或其功能性片段,其包含重链和轻链,其中所述重链和轻链分别包含重链可变区和轻链可变区:
(i)所述重链可变区包含SEQ ID NO:7所示的氨基酸序列或者与其具有至少80%(优选85%、90%、95%、98%或者99%)序列同一性的序列;并且
(ii)所述轻链可变区包含SEQ ID NO:8所示的氨基酸序列或者与其具有至少80%(优选85%、90%、95%、98%或者99%)序列同一性的序列。
在某些具体的实施方案中,所述抗体包含重链和轻链,其中所述重链和轻链分别包含重链可变区和轻链可变区,其中
(i)所述重链可变区包含SEQ ID NO:7所示的氨基酸序列,和/或
(ii)所述轻链可变区包含SEQ ID NO:8所示的氨基酸序列。
特别地,本发明的抗间皮素抗体包含重链和轻链,其中所述重链和轻链分别包含SEQ ID NO:10和SEQ ID NO:9所示的氨基酸序列。
在某些具体的实施方案中,所述抗间皮素抗体或其功能性片段是分离的。
在某些具体的实施方案中,所述抗间皮素抗体或其功能性片段是单克隆抗体、嵌合抗体、人源化抗体、人抗体、单链抗体(scFv)或者双特异性抗体,在某些具体的实施方案中,所述抗间皮素抗体或其功能性片段是单克隆抗体;在某些具体的实施方案中,所述抗间皮素抗体或其功能性片段是人源化抗体;在某些具体的实施方案中,所述抗间皮素抗体或其功能性片段是IgG1κ抗体。
又一方面,本发明提供了一种编码本发明涉及抗体的分离的多核苷酸。
又一方面,本发明提供了分离的多核苷酸的组合,所述组合包括编码本发明抗体或其功能性片段之轻链的多核苷酸和编码本发明抗体或其功能性片段之重链的多核苷酸。
又一方面,本发明提供了表达载体或者表达载体的组合,其包含根据本发明的多核苷酸或者根据本发明的多核苷酸的组合,所述多核苷酸与允许其所编码的多肽在宿主细胞或无细胞表达系统中表达的调节序列有效连接。
又一方面,本发明提供了药物组合物,其包含根据本发明的抗体或其功能性片段和/或根据本发明的缀合物,以及可药用载体。
又一方面,本发明提供了一种治疗或预防癌症的方法,其包括向有此需要的对象施用治疗有效量的根据本发明的抗体、多核苷酸、多核苷酸组合、表达载体、缀合物和/或药物组合物。
又一方面,本发明提供了根据本发明的抗体、多核苷酸、多核苷酸组合、表达载体、缀合物和/或药物组合物在制备用于治疗或预防癌症的药物中的用途。
又一方面,本发明提供了根据本发明的抗体、多核苷酸、多核苷酸组合、表达载体、缀合物和/或药物组合物,其用于治疗或预防癌症。
又一方面,本发明提供了任何上述实施方案中的抗体药物缀合物在制备治疗癌症药物中的用途。
在某些具体的实施方案中,本发明所述的癌症为间皮素阳性癌症。
附图说明
图1显示了RC88-PY-MAA-Val-Cit-PAB-MMAE和RC88-Mc-Val-Cit-PAB-MMAE的SDS-PAGE表征图,该图对RC88抗体与连接子和药物缀合物的偶联情况进行了表征。
图2显示了本发明缀合物的偶联情况,其中A图显示了利用疏水高效液相色谱(HIC-HPLC)法对RC88-PY-MAA-Val-Cit-PAB-MMAE的偶联情况的检测结果;B图显示了利用疏水高效液相色谱(HIC-HPLC)法对RC88-Mc-Val-Cit-PAB-MMAE的偶联情况的检测结果。
图3显示了本发明缀合物的细胞毒作用,其中A图显示了本发明的RC88抗体药物缀合物(RC88-Py-MAA-Val-Cit-PAB-MMAE、RC88-Py-MAA-Val-Cit-PAB-MMAD、RC88-Mc-Val-Cit-PAB-MMAE、RC88-Mc-Val-Cit-PAB-MMAD)在MSLN高表达的Oval-Citar-3细胞中的细胞毒作用曲线;B图显示了未偶联抗体的连接子和细胞毒素偶联物(Py-Val-Cit-PAB-MMAE、Py-Val-Cit-PAB-MMAD、Mc-Val-Cit-PAB-MMAE、Mc-Val-Cit-PAB-MMAD)在MSLN高表达的Oval-Citar-3细胞中的细胞毒作用曲线;C图显示了单独的细胞毒素MMAE、MMAD和阳性对照PTX(Paclitaxel,紫杉醇)在MSLN高表达的Oval-Citar-3细胞中的细胞毒作用曲线。其中横坐标代表了药物的对数浓度,纵坐标代表了在对应药物对数浓度下的最大抑制率。
图4显示了施用RC88抗体(2mg/kg)、RC88抗体药物缀合物(RC88-Py-MAA-Val-Cit-PAB-MMAD、RC88-Py-MAA-Val-Cit-PAB-MMAE、RC88-Mc-Val-Cit-PAB-MMAE、RC88-Mc-Val-Cit-PAB-MMAD,2mg/kg)及MMAE(0.0716mg/kg)的(每周给药1次,共给药3次)荷瘤鼠的体重随天数变化的曲线图,其中横坐标代表了天数,纵坐标代表了荷瘤鼠在实施药物对应天数下的体重。本试验中,对照组为生理盐水(control)和MMAE。
图5显示了施用RC88抗体(2mg/kg)、RC88抗体药物缀合物(RC88-Py-MAA-Val-Cit-PAB-MMAD、RC88-Py-MAA-Val-Cit-PAB-MMAE、RC88-Mc-Val-Cit-PAB-MMAE、RC88-Mc-Val-Cit-PAB-MMAD,2mg/kg)及MMAE(0.0716mg/kg)的(每周给药1次,共给药3次)荷瘤鼠肿瘤体积随天数变化的曲线图,其中横坐标代表了天数,纵坐标代表了荷瘤鼠的肿瘤在实施药物对应天数下的体积。本试验中,对照组为生理盐水(control)和MMAE。
图6显示了施用RC88抗体(2mg/kg)、RC88抗体药物缀合物(RC88-Py-MAA-Val-Cit-PAB-MMAD、RC88-Py-MAA-Val-Cit-PAB-MMAE、RC88-Mc-Val-Cit-PAB-MMAE、RC88-Mc-Val-Cit-PAB-MMAD,2mg/kg)及MMAE(0.0716mg/kg),每周给药1次,共给药3次后荷瘤鼠肿瘤的重量,对照组为生理盐水(control)和MMAE。
图7显示了施用RC88抗体(3mg/kg)、RC88抗体药物缀合物(RC88-Py-MAA-Val-Cit-PAB-MMAE 3mg/kg、1.5mg/kg、0.75mg/kg)、MMAE(0.06mg/kg)、RC88抗体(3mg/kg)+MMAE(0.06mg/kg)、IgG-MMAE 3mg/kg、PTX(紫杉醇,10mg/kg)(每周给药1次,共给药3次(PTX每周给药2次,共给药6次))的荷瘤鼠的体重随天数变化的曲线图,其中横坐标代表了天数,纵坐标代表了荷瘤鼠在实施药物对应天数下的体重。本试验中,对照组为生理盐水(control)和MMAE。
图8显示了施用RC88抗体(3mg/kg)、RC88抗体药物缀合物(RC88-Py-MAA-Val-Cit-PAB-MMAE 3mg/kg、1.5mg/kg、0.75mg/kg)、MMAE(0.06mg/kg)、RC88抗体(3mg/kg)+MMAE(0.06mg/kg)、IgG-MMAE 3mg/kg、PTX(紫杉醇,10mg/kg)(每周给药1次,共给药3次(PTX每周给药2次,共给药6次))的荷瘤鼠的肿瘤体积随天数变化的曲线图,其中横坐标代表了天数,纵坐标代表了荷瘤鼠的肿瘤在实施药物对应天数下的体积。本试验中,对照组为生理盐水(control)和MMAE。
图9显示了RC88抗体药物缀合物(RC88-Py-MAA-Val-Cit-PAB-MMAE)对MSLN高表达的Oval-Citar-3人卵巢癌荷瘤鼠模型的抑瘤作用。
图10显示了通过ELISA实验测定RC88抗体及RC88抗体药物缀合物(RC88-Py-MAA-Val-Cit-PAB-MMAE)与MSLN阳性肿瘤细胞的亲和力曲线。
图11显示了本发明缀合物与靶标的亲和力,其中A图显示了通过酶标法测定RC88抗体及RC88抗体药物缀合物(RC88-Py-MAA-Val-Cit-PAB-MMAE)与MSLN阳性肿瘤细胞的亲和力曲线;B图显示了RC88抗体及RC88抗体药物缀合物(RC88-Py-MAA-Val-Cit-PAB-MMAE)与重组人MSLN蛋白竞争结合曲线。
图12显示了RC88抗体及RC88抗体药物缀合物(RC88-Py-MAA-Val-Cit-PAB-MMAE)和CA125与重组人MSLN蛋白的竞争结合曲线。
具体实施方式
定义
除非另有定义,本文使用的所有科技术语具有本领域普通技术人员所理解的相同含义。关于本领域的定义及术语,专业人员具体可参考Current Protocols in MolecularBiology(Ausubel)。氨基酸残基的缩写是本领域中所用的指代20个常用L-氨基酸之一的标准3字母和/或1字母代码。
尽管本发明的广义范围所示的数字范围和参数近似值,但是具体实施例中所示的数值尽可能准确的进行记载。然而,任何数值本来就必然含有一定的误差,其是由它们各自的测量中存在的标准偏差所致。另外,本文公开的所有范围应理解为涵盖其中包含的任何和所有子范围。例如记载的“1至10”的范围应认为包含最小值1和最大值10之间(包含端点)的任何和所有子范围;也就是说,所有以最小值1或更大起始的子范围,例如1至6.1,以及以最大值10或更小终止的子范围,例如5.5至10。另外,任何称为“并入本文”的参考文献应理解为以其整体并入。
另外应注意,如本说明书中所使用的,单数形式包括其所指对象的复数形式,除非清楚且明确的限于一个所指对象。术语“或”可与术语“和/或”互换使用,除非上下文另有清楚指明。
本文使用的术语“间皮素”,也称Mesothelin、MSLN,指源自细胞中间皮素前体蛋白加工的任何天然、成熟间皮素。该术语包括来自任何脊椎动物来源的间皮素,包括哺乳动物诸如灵长类动物(例如人和猿猴)和啮齿类动物(例如小鼠和大鼠),除非另有说明,该术语还包括间皮素的天然存在变体,例如剪接变体或等位变体。
本文使用的术语“药物组合物”、“组合药物”和“药物组合”可互换地使用,其表示组合在一起以实现某种特定目的的至少一种药物以及任选地可药用载体或辅料的组合。在某些实施方案中,所述药物组合物包括在时间和/或空间上分开的组合,只要其能够共同作用以实现本发明的目的。例如,所述药物组合物中所含的成分(例如根据本发明的抗体、核酸分子、核酸分子组合和/或缀合物)可以以整体施用于对象,或者分开施用于对象。当所述药物组合物中所含的成分分开地施用于对象时,所述成分可以同时或依次施用于对象。优选地,所述可药用载体是水、缓冲水溶液、等渗盐溶液如PBS(磷酸盐缓冲液)、葡萄糖、甘露醇、右旋葡萄糖、乳糖、淀粉、硬脂酸镁、纤维素、碳酸镁、0.3%甘油、透明质酸、乙醇或聚亚烷基二醇如聚丙二醇、甘油三酯等。所用可药用载体的类型尤其依赖于根据本发明的组合物是否配制为用于口服、鼻、皮内、皮下、肌内或静脉施用。根据本发明的组合物可包含润湿剂、乳化剂或缓冲液物质作为添加剂。
根据本发明的药物组合物、疫苗或者药物制剂可通过任何适宜的途径施用,例如可口服、鼻、皮内、皮下、肌内或静脉内施用。
本文使用的术语“治疗剂”表示能够起到治疗作用(例如治疗、预防、缓解或抑制任何疾病和/或病症)的任何物质或实体(entity),其包括但不限于:化学治疗剂、放射治疗剂、免疫治疗剂、热治疗剂(thermally therapeutic agent)等。
本文使用的“CDR区”或“CDR”是指免疫球蛋白的重链和轻链的高变区,如Kabat etal.所定义(Kabat et al.,Sequences of proteins of immunological interest,5thEd.,U.S.Department ofHealth and Human Services,NIH,1991,以及以后版本)。存在三个重链CDR和三个轻链CDR。根据情况,本文所用术语CDR或CDRs是为了指示这些区域之一、或者这些区域的几个或者甚至全部,所述区域包含通过抗体对抗原或其识别表位的亲和力而负责结合的大部分氨基酸残基。
对本发明来说,两种核酸或者氨基酸序列间的“一致性”、“同一性”或“相似性”是指,在最佳比对(最优比对)后所获得的、待比较的两序列之间相同核苷酸或相同氨基酸残基的百分数,该百分数是纯粹统计学的并且两种序列间的差异随机分布并覆盖其全长。两种核酸或者氨基酸序列之间的序列比较通常是在以最优方式使它们匹配以后,通过比较这些序列而进行,所述比较能够通过区段或者通过“比较窗”实施。除了能够手工实施外,用于比较序列的最优比对,还能够通过Smith和Waterman(1981)[Ad.App.Math.2:482]的局部同源性算法、通过Neddleman和Wunsch的(1970)[J.MoI.Biol.48:443]局部同源性算法、通过Pearson和Lipman的(1988)[Proc.Natl.Acad.Sci.USA 85:2444)相似性搜索方法、通过使用这些算法的计算机软件实施(GAP、BESTFIT、FASTA和TFASTA in the WisconsinGenetics Software Package,Genetics Computer Group,575Science Dr.,Madison,WI,或者通过BLAST N or BLAST P比较软件)。
本文使用的“治疗有效量”或“有效量”是指足以显示其对于所施用对象益处的剂量。施用的实际量,以及施用的速率和时间过程会取决于所治疗者的自身情况和严重程度。治疗的处方(例如对剂量的决定等)最终是全科医生及其它医生的责任并依赖其做决定,通常考虑所治疗的疾病、患者个体的情况、递送部位、施用方法以及对于医生来说已知的其它因素。
本文所使用的术语“对象”是指哺乳动物,如人类,但也可以是其它动物,如野生动物(如苍鹭、鹳、鹤等),家畜(如鸭、鹅等)或实验动物(如猩猩、猴子、大鼠、小鼠、兔子、豚鼠、土拨鼠、地松鼠等)。
本文所使用的“抗体”以最广义使用,并且涵盖各种抗体结构,包括但不限于单克隆抗体、多克隆抗体、多特异性抗体(例如双特异性抗体)、和抗体片段,特别的,本文所使用的“抗体”指包含通过二硫键而互连的至少两条重(H)链和两条轻(L)链的蛋白。每条重链包含一重链可变区(缩写为VH)和一重链恒定区。该重链恒定区包含三个域(domain),CH1、CH2和CH3。每条轻链包含一轻链可变区(缩写为VL)和一轻链恒定区。该轻链恒定区包含一个域,CL。VH和VL区域还可再细分为具有高可变性的多个区,被称为互补决定区(CDR),其间散布有更为保守的被称为框架区(FR)的多个区域。每个VH和VL均由三个CDR和四个FR构成,按照以下顺序从氨基端至羧基端排布:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。重链和轻链的这些可变区包含与抗原相互作用的结合域。抗体的恒定区可介导免疫球蛋白与宿主的组织或因子结合,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成分(Clq)。嵌合或人源化抗体也涵盖在根据本发明的抗体中。
术语“人源化抗体”是指一种抗体,其包含来源于非人源抗体的CDR区、并且该抗体分子的其他部分来源于一种(或几种)人抗体。而且,为了保留结合亲和力,可以修饰骨架(称为FR)区段的一些残基(Jones et al.,Nature,321:522-525,1986;Verhoeyen et al.,Science,239:1534-1536,1988;Riechmann et al.,Nature,332:323-327,1988)。通过本领域技术人员已知的技术可以制备根据本发明的人源化抗体或其片段(例如,描述于文件Singer et al.,J.Immun.150:2844-2857,1992;Mountain et al.,Biotechnol.Genet.Eng.Rev.,10:1-142,1992;或Bebbington et al.,Bio/Technology,10:169-175,1992)。
术语“嵌合抗体”系指以下抗体,其中的可变区序列来自一物种而恒定区序列来自另一物种,例如可变区序列来自小鼠抗体而恒定区序列来自人抗体的抗体。通过使用基因重组技术可以制备根据本发明的嵌合抗体或其片段。例如,所述嵌合抗体可以通过克隆重组DNA来生产,所述重组DNA包含启动子和编码根据本发明的非人尤其是鼠单克隆抗体可变区的序列、以及编码人抗体恒定区的序列。由这种重组基因编码的本发明嵌合抗体将是,例如,鼠-人嵌合体,该抗体的特异性由来源于鼠DNA的可变区确定,并且其同种型由来源于人DNA的恒定区来确定。对于制备嵌合抗体的方法,例如,可以参考文件Verhoeyn et al.(BioEssays,8:74,1988)。
术语“单克隆抗体”系指具有单一分子组成的抗体分子的制备物。单克隆抗体组合物显示出对于特定表位的单一结合特异性和亲和性。
本文所使用的术语“功能性片段”是指抗体片段由其来源抗体的重或轻可变链的部分序列构成或者包含它们,所述部分序列足以保留与其来源抗体相同的结合特异性和充分的亲和力,优选至少等于其来源抗体亲和力的1/100,在更优选方式中至少等于1/10。这种功能片段将包含最少5个氨基酸,优选其来源的抗体序列的10、15、25、50和100个连续氨基酸。
本文所使用的术语“DAR”是指在抗体药物缀合物中的药物-抗体比(Drug-Antibody Ratio),其表示与一个抗体相缀合的药物的平均数量。优选地,本发明的抗体药物缀合物具有约2至约6的DAR值,例如约2、2.5、3、3.5、3.6、3.7、3.8、3.9、4、4.1、4.2、4.3、4.4、4.5、5、5.5、6或其任意两者的区间。
通常,为了制备单克隆抗体或其功能片段,尤其是鼠源的单克隆抗体或其功能片段,可以参考尤其描述在手册“Antibodies”中的技术(Harlow and Lane,Antibodies:ALaboratory Manual,Cold Spring Harbor Laboratory,Cold Spring Harbor NY,pp.726,1988)或者参考Kohler和Milstein描述的从杂交瘤细胞制备的技术(Nature,256:495-497,1975)。
根据本发明的单克隆抗体或者抗体药物缀合物可以是纯化的,例如可以在亲和柱上纯化,已经预先在所述亲和柱上固定了MSLN抗原或其包含可被根据本发明所述抗体特异性识别的表位的片段之一。更具体而言,所述单克隆抗体可以如此纯化,通过蛋白质A和/或G色谱,接或不接目的在于消除残留蛋白质污染物以及DNA和LPS的离子交换色谱,其本身接或不接在Sepharose凝胶上的排阻色谱以消除由于二聚体或其他多聚体存在而潜在的聚集体。在更优选的方式中,全部这些技术可以同时或者连续使用。
本文使用的术语“海兔毒素肽(dolastatin)”是指分离自一种海洋生物截尾海兔(Dollabella auricularia)的多肽,其包括但不限于海兔毒素肽10(dolastatin 10)和海兔毒素肽15(dolastatin 15)。海兔毒素肽是有丝分裂抑制剂,其表现出强的抗癌活性,因此被作为抗癌药物的候选。研究人员进一步发现和合成了许多海兔毒素肽的衍生物,例如MMAE和MMAF。
本文使用的术语“连接子”是指抗体药物缀合物(即ADC)中将抗体与药物相连接的部分,其可以是可切割的或者不可切割的。可切割的连接子(即可断裂的连接子或生物可降解连接子)可以在靶标细胞内或其上断裂,从而释放药物。在某些实施方案中,本发明的连接子具有非常好的稳定性,大大减少了药物在递送到靶标过程中(例如在血液中)的释放,从而减少了副作用和毒性。在一些特定实施方案中,本发明的连接子选自可切割的连接子,例如基于二硫化物的连接子(其在巯基浓度更高的肿瘤细胞中选择性断裂)、肽连接子(其被肿瘤细胞中的酶所切割)、腙连接子。在另一些特定实施方案中,本发明的接头选自不可切割的连接子(即,不可断裂的连接子),例如硫醚连接子。在又一些实施方案中,本发明的连接子为可断裂连接子与不可断裂连接子的组合。优选地,本发明的连接子选自Mc-Val-Cit-PAB和Py-MAA-Val-Cit-PAB。
抗MSLN抗体
本发明的抗体药物缀合物中的抗体的特征在于特异性结合人MSLN。优选的是,该抗体以高亲和力结合MSLN,例如,以1×10-7M或更小的KD。抗MSLN抗体优选显示以下特性的一或多种:
(a)以1×10-7M或更小的KD(例如,5×10-8M或更小、2×10-8M或更小、5×10-9M或更小、4×10-9M或更小、3×10-9M或更小、2×10-9M或更小)结合人MSLN;
(b)结合MSLN高表达的Oval-Citar-3细胞,例如以2000ng/ml或更小的EC50(例如,1000ng/ml或更小、500ng/ml或更小、400ng/ml或更小、300ng/ml或更小、250ng/ml或更小、200ng/ml或更小、150ng/ml或更小、100ng/ml或更小、50ng/ml或更小、40ng/ml或更小、30ng/ml或更小、20ng/ml或更小、10ng/ml或更小、5ng/ml或更小),优选地所述EC50使用流式细胞术或酶标法进行测定;和
(c)抑制表达MSLN细胞的体内生长。
单克隆抗体RC88
优选用于本发明的抗体药物缀合物中的抗体为人单克隆抗体RC88。RC88的VH和VL氨基酸序列分别显示在SEQIDNO:7和8。
在另一方面中,本发明的抗体可包括RC88的重链和轻链CDR1、CDR2和CDR3,或它们的组合。RC88的VHCDR1、VHCDR2、VHCDR3的氨基酸序列分别显示在SEQ ID NO:1-3中。RC88的VLCDR1、VLCDR2、VLCDR3的氨基酸序列分别显示在SEQ ID NO:4-6中。CDR区系用Kabat系统进行说明(Kabat,E.A.,etal..(1991).Sequences of Proteins of ImmunologicalInterest,Fifth Edition,U.S.Department of Health and Human Services,NIHPublication NO:91-3242;以下称之为“Kabat‘3242”)。
实施例
以下是本发明的方法和组合物的实施例。应当理解,鉴于上文提供的定义及一般描述,可以实施各种其他实施方案。
实施例1抗间皮素抗体
使用标准方法产生免疫动物,从而产生本发明的抗间皮素抗体,例如可参见Kohler&Milstein,(1975)Nature 256:495-497,Kozbor et al.(1983)Immunol.Today 4:72以及Cole,et al.in MONOCLONALANTIBODIES AND CANCER THERAPY,Alan R.Liss,Inc.,1985,pp.77-96。
使用已知技术从细胞中分离并纯化间皮素,并将其作为免疫原来免疫动物,例如可参见Zola,MONOCLONAL ANTIBODIES:PREPARATION AND USE OF MONOCLONAL ANTIBODIESAND ENGINEERED ANTIBODY DERIVATIVES(BASICS:FROM BACKGROUND TO BENCH)Springer-Verlag Ltd.,New York,2000;BASIC METHODS IN ANTIBODY PRODUCTION ANDCHARACTERIZATION,Chapter 11,"Antibody Purification Methods,"Howard andBethell,Eds.,CRC Press,2000;ANTIBODY ENGINEERING(SPRINGER LAB MANUAL.),Kontermann and Dubel,Eds.,Springer-Verlag,2001。
从免疫动物中取出脾细胞,将其与骨髓瘤细胞系融合,得到杂交瘤。然后,通过筛选获得高结合亲和力的抗MSLN抗体。
通过移植轻链或重链CDR到人的IgG1或重链框架区来人源化鼠抗MSLN单克隆抗体。鼠源抗MSLN抗体轻链和重链的CDR用Kabat系统确定。通过对抗体可变区数据库比对,我们确定了与鼠源MSLN抗体具有很高同源性的人IgG1框架区。由此,我们设计了不同的人源化MSLN抗体的轻链可变区序列和不同的人源化抗MSLN的重链可变区序列。根据这样的设计,我们合成了人源化重链和轻链可变区序列,将人源化MSLN抗体轻链可变区与人kappa恒定区通过PCR融合,得到人源化MSLN轻链全长;将人源化MSLN重链可变区与IgG恒定区用PCR方法融合,得到人源化MSLN重链全长。不同轻重链组合并表达,纯化后的人源化抗体与人-鼠嵌合抗体进行ELISA结合亲和力比较,筛选得到候选人源化抗体(命名为RC88抗体)。
下面表3示出了RC88抗体轻链和重链的CDR氨基酸序列。
表3.RC88抗体重链和轻链的氨基酸序列
RC88抗体重链可变区氨基酸序列(SEQ ID NO:7):
RC88抗体轻链可变区氨基酸序列(SEQ ID NO:8):
RC88抗体的轻链和重链氨基酸序列分别如序列9(SEQ ID NO:9)和序列10(SEQ IDNO:10)所示。
实施例2抗体药物缀合物(ADC)的制备
实施例2a.连接子-药物缀合物的制备
①化合物1(Py-MAA-Val-Cit-PAB-OH)的合成
将化合物Py-MAA(1,3,5-三丙烯酰基六氢-1,3,5-三嗪-巯基乙酸,10.00g,29.3mmol)溶于DMF(200mL)中,加入HATU(16.73g,44.0mmol),Val-Cit-PAB-OH(9.20g,23.4mmol),DIPEA(15.32mL,87.9mmol),室温搅拌24小时,TLC监测反应进程。反应完后,减压旋蒸除去溶剂,粗品用制备型高效液相进行纯化,制备液减压旋蒸后得到化合物1(6.67g,32.4%,白色固体粉末)。
②化合物2(Py-MAA-Val-Cit-PAB-PNP)的合成
化合物1(7.02g,10.0mmol)溶于DMF(200mL)中,加入NPC(二(对硝基苯)碳酸酯),4.56g,15.0mmol)和DIPEA(2.09mL,12mmol),室温反应5小时,TLC检测反应进程。反应完成后,将反应液倒入石油醚(1500mL)中,搅拌,过滤,所得滤饼用石油醚洗涤(150mL×3),抽干,得到类白色固体粉末(6.57g,75.7%)。
③化合物3(Py-MAA-Val-Cit-PAB-MMAE)的合成
化合物2(1.74g,2.2mmol)溶于20mL DMF中,氮气保护下加入MMAE(1.44g,2.0mmol),HOBt(0.27g,2.0mmol),DIPEA(0.70mL,4.0mmol)和吡啶(4mL)。室温搅拌24小时,TLC监测反应进程。反应结束后,用制备型高效色谱进行纯化,制备液减压旋蒸后得到化合物3(白色固体粉末,1.35g,46.7%)。LC-MS m/z(ES+),1446.35(M+H)+,IR(3334.32cm-1,2965.9cm-1,1652.70cm-1,1538.92cm-1,1436.71cm-1)。
④化合物4(Py-MAA-Val-Cit-PAB-MMAD)的合成
化合物2(0.87g,1.1mmol)溶于10mL DMF中,氮气保护下加入MMAD(0.77g,1.0mmol),HOBt(0.14g,1.0mmol),DIPEA(0.35mL,2.0mmol)和吡啶(2mL)。室温搅拌24小时,TLC监测反应进程。反应结束后,用制备型高效色谱进行纯化,制备液减压旋蒸后得到化合物4(白色固体粉末,0.65g,43.5%)。LC-MS m/z(ES+),1499.76(M+H)+。
⑤化合物6(Mc-Val-Cit-PAB-PNP)的合成
化合物5(Mc-Val-Cit-PAB,4.58g,8.0mmol)溶于DMF(100mL)中,加入NPC(二(对硝基苯)碳酸酯),3.65g,12.0mmol)和DIPEA(1.70mL,9.6mmol),室温反应5小时,TLC检测反应进程。反应完成后,将反应液倒入石油醚(1000mL)中,搅拌,过滤,所得滤饼用石油醚洗涤(60mL×3),抽干,得到类白色固体粉末(5.04g,85.2%)。
⑥化合物7(Mc-Val-Cit-PAB-MMAE)的合成
化合物6(1.19g,1.6mmol)溶于12mL DMF中,氮气保护下加入MMAE(1.08g,1.5mmol),HOBt(0.21g,1.5mmol),DIPEA(0.55mL,3.0mmol)和吡啶(2.5mL)。室温搅拌24小时,TLC监测反应进程。反应结束后,用制备型高效色谱进行纯化,制备液减压旋蒸后得到化合物7(白色固体粉末,0.891g,45.1%)。LC-MS m/z(ES+),1316.18(M+H)+。
⑦化合物8(Mc-Val-Cit-PAB-MMAD)的合成
化合物6(0.74g,1.1mmol)溶于10mL DMF中,氮气保护下加入MMAD(0.77g,1.0mmol),HOBt(0.14g,1.0mmol),DIPEA(0.35mL,2.0mmol)和吡啶(2mL)。室温搅拌24小时,TLC监测反应进程。反应结束后,用制备型高效色谱进行纯化,制备液减压旋蒸后得到化合物8(白色固体粉末,0.59g,42.8%)。LC-MS m/z(ES+),1369.38(M+H)+。
实施例2b.抗体药物缀合物的制备
将10mg/mL的RC88抗体、10mmol/L的DTPA(Diethylene triamine pentacetateacid,二乙基三胺五乙酸)以及5摩尔倍数的5mmol/L的TCEP(Tris-2-carboxyethyl-phosphine,三(2-羧乙基)膦)加入PCR管中,25℃搅拌反应2h,再于0℃下加入25%的DMSO(dimethyl sulfoxide,二甲亚砜)以及5摩尔倍数的5mmol/L的药物(化合物3、4、7或8),25℃搅拌反应10h。反应结束后,用PBS缓冲液离心超滤3次,纯化去除残余未反应药物以及DMSO等游离小分子,并且利用SDS-PAGE电泳和疏水高效液相色谱(HIC-HPLC)法检测偶联情况。对RC88-PY-MAA-Val-Cit-PAB-MMAE和RC88-Mc-Val-Cit-PAB-MMAE用还原SDS-PAGE进行表征,此次实验采用Novex公司的NuPAGE预制胶,每个样品总上样体积为10μL,其结果如图1所示。RC88-PY-MAA-Val-Cit-PAB-MMAE由于桥接连接子将还原后的二硫键又用共价键连接起来,因此存在不同情形的条带,其中150kDa为完整抗体(LHHL),125kDa表示有一个轻链没有被偶联起来(LHH),100kDa为偶联了两个重链(HH),75kDa为偶联了一个轻链一个重链(LH),50kDa和25kDa分别为重链和轻链。由于RC88-Mc-Val-Cit-PAB-MMAE不是桥接的连接子,二硫键还原成两个巯基后分别与两个连接子-毒素偶联,因此还原SDS-PAGE仅显示50kDa和25kDa两个条带。用疏水高效液相色谱(HIC-HPLC)法对RC88-PY-MAA-Val-Cit-PAB-MMAE和RC88-Mc-Val-Cit-PAB-MMAE的偶联情况进行了检测,结果分别如图2A和图2B所示,结果显示DAR值分别为3.95(RC88-PY-MAA-Val-Cit-PAB-MMAE)和3.9(RC88-Mc-Val-Cit-PAB-MMAE)。
实施例3高表达MSLN的Oval-Citar-3细胞的构建
将生长状态良好的Oval-Citar-3细胞(ATCC)以3x105/个孔接种至6孔板,贴壁过夜后,弃掉原培养基,加入含10μg/mL Polybrene(sigma)的新鲜培养基400μL,同时加入合适浓度的含有人MSLN编码序列的慢病毒载体(pRRL-cmv)600μL,混匀后继续培养24hr。培养结束后,更换新鲜培养基继续扩大培养,使用流式细胞仪选择阳性细胞。将所选的阳性细胞扩大培养,经流式细胞仪对MSLN表达量的分析后,选取MSLN表达量最高的细胞用于后续实验(下文称其为Oval-Citar-3-MSLN)。
实施例4RC88抗体及RC88抗体药物缀合物及相应连接子-药物、药物的细胞毒活性检测
取生长状态良好的Oval-Citar-3-MSLN细胞加入96孔细胞培养板(5×104个/mL,100μL/孔),CO2恒温培养箱37℃孵育过夜。RC88抗体、RC88抗体药物缀合物(RC88-Py-MAA-Val-Cit-PAB-MMAE、RC88-Py-MAA-Val-Cit-PAB-MMAD、RC88-Mc-Val-Cit-PAB-MMAE、RC88-Mc-Val-Cit-PAB-MMAD)及相应连接子-药物(Py-Val-Cit-PAB-MMAE、Py-Val-Cit-PAB-MMAD、Mc-Val-Cit-PAB-MMAE、Mc-Val-Cit-PAB-MMAD)、药物(MMAE、MMAD)、PTX(Paclitaxel,紫杉醇)用完全培养基分别稀释,稀释浓度分别为:RC88抗体、RC88抗体药物缀合物(RC88-Py-MAA-Val-Cit-PAB-MMAE、RC88-Py-MAA-Val-Cit-PAB-MMAD、RC88-Mc-Val-Cit-PAB-MMAE、RC88-Mc-Val-Cit-PAB-MMAD)的终浓度为:0.32、1.6、8、16、32、64、128、640、3200ng/mL,连接子-药物(Py-Val-Cit-PAB-MMAE、Py-Val-Cit-PAB-MMAD、Mc-Val-Cit-PAB-MMAE、Mc-Val-Cit-PAB-MMAD)的终浓度为:0.4、2、10、20、40、80、160、800、4000ng/mL,药物(MMAE、MMAD)的终浓度为:0.0016、0.008、0.04、0.2、0.4、0.8、1.6、8、40ng/mL,PTX(Paclitaxel,紫杉醇)的终浓度:0.004、0.02、0.098、0.3、0.89、2.67、8、40、200ng/mL。稀释后加入96板(100μL/孔),设置空白组(未加药的等量培养基)和三个对照组,CO2恒温培养箱37℃孵育72h。加入含CCK-810μL的培养基(不含FBS)100μL/孔,CO2恒温培养箱37℃孵育2-4hr,酶标仪读取450nm处OD值,抑制率计算公式为:IR%=(OD空白-OD药物)×100/OD空白。使用Prism软件将抑制率作为y值,药物浓度作为x值进行四参数曲线拟合,并记录抑制率为介于最大抑制率和最小抑制率中间的值所对应的药物浓度值(软件默认为IC50值),结果见图3和表4。结果显示,RC88-Py-MAA-Val-Cit-PAB-MMAD、RC88-Mc-Val-Cit-PAB-MMAD、RC88-Py-MAA-Val-Cit-PAB-MMAE、RC88-Mc-Val-Cit-PAB-MMAE均能够有效抑制Oval-Citar-3-MSLN)的生长。
表4RC88抗体、RC88抗体药物缀合物及相应连接子-药物、药物细胞毒作用IC50值、最大抑制率结果(N=3)
实施例5RC88抗体及RC88抗体药物缀合物对MSLN高表达的Oval-Citar-3人卵巢癌荷瘤鼠模型的抑瘤实验
取生长状态良好的Oval-Citar-3-MSLN细胞(2×106个),接种于裸鼠(常州卡文斯实验动物有限公司,合格证编号:201611240,许可证号:SCXK(苏)2011-0003)皮下,待肿瘤体积生长至约100-400mm3后将动物随机分组。施用RC88抗体(2mg/kg)、RC88抗体药物缀合物(RC88-Py-MAA-Val-Cit-PAB-MMAD、RC88-Py-MAA-Val-Cit-PAB-MMAE、RC88-Mc-Val-Cit-PAB-MMAE、RC88-Mc-Val-Cit-PAB-MMAD,2mg/kg)及MMAE(0.0716mg/kg),每周给药1次,共给药3次,阴性对照组同时给等量的生理盐水,结果见图4、5和6。
结果显示RC88抗体及RC88抗体药物缀合物不影响荷瘤鼠体重增加;RC88抗体药物缀合物(RC88-Py-MAA-Val-Cit-PAB-MMAD、RC88-Py-MAA-Val-Cit-PAB-MMAE、RC88-Mc-Val-Cit-PAB-MMAE、RC88-Mc-Val-Cit-PAB-MMAD,2mg/kg)均表现出明显的抑制荷瘤鼠移植瘤作用,而RC88抗体的抑瘤作用不明显。
实施例6RC88抗体药物缀合物对MSLN高表达的Oval-Citar-3人卵巢癌荷瘤鼠模型的抑瘤实验
取正常生长的Oval-Citar-3-MSLN细胞(2×106个),接种于裸鼠(常州卡文斯实验动物有限公司,合格证编号:201611240,许可证号:SCXK(苏)2011-0003)皮下,待肿瘤体积生长至约100-400mm3后将动物随机分组。实施所测试药物RC88抗体(3mg/kg)、RC88抗体药物缀合物(RC88-Py-MAA-Val-Cit-PAB-MMAE 3mg/kg、1.5mg/kg、0.75mg/kg)MMAE 0.06mg/kg、RC88抗体(3mg/kg)+MMAE(0.06mg/kg)、人血清IgG-MMAE 3mg/kg、PTX(Paclitaxel,紫杉醇)10mg/kg,每周给药1次,共给药3次(PTX每周给药2次,共给药6次),阴性对照组同时给等量的生理盐水,结果见图7、8、9。试验结果显示RC88抗体药物缀合物给药剂量为3mg/kg组和1.5mg/kg组荷瘤鼠肿瘤在第一次给药7天后明显减小,3mg/kg组至给药10天后无可见肿瘤,1.5mg/kg组至给药17天后无可见肿瘤,0.75mg/kg组在给药3次的情况下,肿瘤生长依然比较快,至给药21天,肿瘤体积与对照(生理盐水)组比较无统计学差异(P>0.05),且T/C>40%。紫杉醇(PTX)组至给药21天,有两只荷瘤鼠的肿瘤完全消除(CR),肿瘤体积和RTV与对照(生理盐水)组比较有统计学差异(P<0.05),且T/C<40%。紫杉醇(PTX)组与RC88抗体药物缀合物给药剂量3mg/kg组和1.5mg/kg组比较无统计学差异。RC88抗体、MMAE、RC88抗体+MMAE、IgG-MMAE与对照(生理盐水)组比较无统计学差异(P>0.05)。
实施例7RC88抗体及RC88抗体药物缀合物与MSLN阳性肿瘤细胞的亲和力检测
用流式细胞仪检测RC88抗体及RC88抗体药物缀合物(RC88-Py-MAA-Val-Cit-PAB-MMAE)与MSLN阳性肿瘤细胞的亲和力,取对数生长期Oval-Citar-3-MSLN细胞于1.5mL EP管中(每组4×105个),1500rpm离心5min,PBS充分洗涤一次,弃去上清液部分;用多聚甲醇(200μL 4%)重悬细胞,25℃固定15min,PBS充分洗涤一次,2500rpm离心3min,弃去上清液部分;用冷的1%BSA-PBS(牛血清白蛋白-PBS)缓冲液将RC88抗体以及RC88抗体药物缀合物从10000ng/mL 3倍梯度稀释至1.52ng/mL,并分别取用各浓度溶液200μL重悬细胞,空白对照组直接用冷的1%BSA-PBS重悬,阴性对照组用1%BSA配制的浓度为5μg/mL的hIgG(中科晨宇)重悬细胞,4℃孵育30min,每10min颠倒混匀一次,使细胞孵育均匀;孵育结束,用冷的PBS洗一次,2500rpm,4℃离心3min,弃上清;每管加入冷的PBS 1:200稀释的FITC(Fluorescein Isothiocyanate,异硫氰酸荧光素)标记的羊抗人IgG Fcγ(JacksonImmunoResearch)200μL,4℃孵育30min,每10min颠倒混匀一次,使细胞孵育均匀。孵育结束,用冷的PBS洗一次,2500rpm,4℃离心5min,弃上清;400μLPBS重悬细胞,转移到流式细胞仪(BD Calibur)进行检测,其结果见图10。结果表明,RC88抗体及RC88抗体药物缀合物(RC88-Py-MAA-Val-Cit-PAB-MMAE)均与MSLN阳性肿瘤细胞有强结合亲和力,EC50值分别为153.5ng/mL和251.4ng/mL。
实施例8RC88抗体及RC88抗体药物缀合物与MSLN阳性肿瘤细胞的结合活性检测
用酶标法检测RC88抗体及RC88抗体药物缀合物(RC88-Py-MAA-Val-Cit-PAB-MMAE)与MSLN阳性肿瘤细胞的结合活性,取对数生长期Oval-Citar-3-MSLN,加入96孔细胞培养板(4×105个/mL,100μL/孔),CO2恒温培养箱37℃孵育过夜,弃去上清液部分,以0.05%PBST缓冲液洗板3次(250μL/孔);每孔加入4%多聚甲醛100μL,25℃固定30分钟后,以0.05%PBST缓冲液洗板3次(250μL/孔);每孔加入250μL3%BAS-PBST(牛血清白蛋白-PBST)缓冲液,室温封闭2小时后,以0.05%PBST缓冲液充洗板3次(250μL/孔);加样:1)结合曲线:用1%BAS-PBST缓冲液将RC88抗体及RC88抗体药物缀合物从3000ng/mL 3倍梯度稀释至0.05ng/mL后加入96孔板(100μL/孔);2)竞争曲线:将重组人MSLN蛋白(义翘神州)用1%BAS-PBST从10000ng/mL稀释至0.51ng/mL,RC88抗体及RC88抗体药物缀合物稀释为20ng/mL后,与MSLN蛋白稀释液等体积混合后,以100μL/孔加入96孔板;25℃孵育1小时后,洗板3次;每孔加入1%BAS-PBST稀释的HRP(Horseradish Peroxidase,辣根过氧化物酶)标记的羊抗人IgG Fc(Bethyl)(1:2000),25℃孵育1小时后,洗板3次;TMB显色试剂盒(康为世纪)避光显色5-10分钟,2M硫酸终止,用酶标仪读板,其结果见图11。试验结果表明RC88抗体及RC88抗体药物缀合物均与MSLN阳性肿瘤细胞有较强结合,RC88抗体药物缀合物较RC88抗体略有下降,但并没有显著性差异,EC50值分别为11.0±0.81ng/mL和19.7±5.80ng/mL。通过与重组人MSLN蛋白的竞争实验可证明RC88抗体及RC88抗体药物缀合物与Oval-Citar-3-MSLN细胞表面的MSLN结合具有特异性。
实施例9RC88抗体及RC88抗体药物缀合物、CA125与MSLN的竞争性结合
利用ELISA法检测RC88抗体及RC88抗体药物缀合物(RC88-Py-MAA-Val-Cit-PAB-MMAE)、CA125与MSLN的竞争性结合能力。用重组蛋白MSLN(义翘神州,200ng/mL)包被ELISA板。加样:将RC88抗体及RC88抗体药物缀合物用1%BAS-PBST(牛血清白蛋白-PBST)缓冲液从20μg/mL起梯度稀释10个点(50μL/孔),将重组蛋白CA125(his tag,R&D)用1%BAS-PBST缓冲液稀释至200ng/mL(50μL/孔),反应总体系100μL/孔,稀释二抗(小鼠抗his单抗,R&D)5000倍,100μL/孔,TMB(3,3',5,5'-Tetramethylbenzidine,3,3',5,5'-四甲基联苯胺)显色5-7min,之后2M硫酸终止反应,用酶标仪450nm处读板,其结果见图12。结果显示,随着RC88抗体及RC88抗体药物缀合物浓度的升高,重组CA125蛋白与重组人MSLN蛋白的结合降低,表明RC88抗体及RC88抗体药物缀合物可以阻断重组人CA125蛋白与重组人MSLN蛋白的结合。
以上描述地仅是优选实施方案,其只作为示例而不限制实施本发明所必需特征的组合。所提供的标题并不意指限制本发明的多种实施方案。术语例如“包含”、“含”和“包括”不意在限制。此外,除非另有说明,没有数词修饰时包括复数形式,以及“或”、“或者”意指“和/或”。除非本文另有定义,本文使用的所有技术和科学术语的意思与本领域技术人员通常理解的相同。
本申请中提及的所有公开物和专利通过引用方式并入本文。不脱离本发明的范围和精神,本发明的所描述的方法和组合物的多种修饰和变体对于本领域技术人员是显而易见的。虽然通过具体的优选实施方式描述了本发明,但是应该理解所要求保护的本发明不应该被不适当地局限于这些具体实施方式。事实上,那些对于相关领域技术人员而言显而易见的用于实施本发明的所描述的模式的多种变体意在包括在随附的权利要求的范围内。
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<110> 荣昌生物制药(烟台)有限公司
<120> 一种抗间皮素抗体及其抗体药物缀合物
<130> RC088-001
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Claims (16)
1.一种抗体药物缀合物,其具有式Ab-(L-D)n,其中:
(a)Ab为特异性结合MSLN的抗体或其功能性片段;
(b)L为连接子或不存在;
(c)D为治疗剂;并且
(d)n为1、2、3、4、5、6、7或8。
2.根据权利要求1所述的抗体药物缀合物,其中所述特异性结合MSLN的抗体包含重链和轻链,其中
(i)所述重链包含三个CDR区,其中所述CDR区中至少一个的氨基酸序列具有如SEQ IDNO:1、2或3所示的氨基酸序列或者与其具有至少80%序列同一性的序列;并且
(ii)所述轻链包含三个CDR区,其中所述CDR区中至少一个的氨基酸序列具有如SEQ IDNO:4、5或6所示的氨基酸序列或者与其具有至少80%序列同一性的序列。
3.根据权利要求1-2中任一项所述的抗体药物缀合物,其中所述特异性结合MSLN的抗体包含重链可变区和轻链可变区,其中
(i)所述重链可变区包含SEQ ID NO:7所示的氨基酸序列或者与其具有至少80%序列同一性的序列;并且
(ii)所述轻链可变区包含SEQ ID NO:8所示的氨基酸序列或者与其具有至少80%序列同一性的序列。
4.根据权利要求1-3中任一项所述的抗体药物缀合物,其中所述抗体是单克隆抗体、嵌合抗体、人源化抗体、单链抗体(scFv)或者双特异性抗体。
5.根据权利要求1-4中任一项所述的抗体药物缀合物,其中所述治疗剂为海兔毒素肽,优选MMAD、MMAE或MMAF,更优选MMAE。
6.根据权利要求1-5中任一项所述的抗体药物缀合物,其中所述连接子与抗体通过抗体上的巯基连接。
7.根据权利要求1-6中任一项所述的抗体药物缀合物,其中
所述连接子具有如下式所示结构:
或者
所述连接子具有如下式所示结构:
8.根据权利要求1-7中任一项所述的任一抗体药物缀合物,其结构如下式任一所示:
9.一种能够特异性结合间皮素的抗体或其功能性片段,其中所述抗体包含重链和轻链,其中
(i)所述重链包含三个CDR区,所述CDR区中至少一个的氨基酸序列具有如SEQ ID NO:1、2或3所示的氨基酸序列或者与其具有至少80%序列同一性的序列;
(ii)所述轻链包含三个CDR区,所述CDR区中至少一个的氨基酸序列具有如SEQ ID NO:4、5或6所示的氨基酸序列或者与其具有至少80%序列同一性的序列。
10.根据权利要求9所述的抗体或其功能性片段,其中所述抗体包含重链可变区和轻链可变区,
(i)所述重链可变区包含SEQ ID NO:7所示的氨基酸序列或者与其具有至少80%序列同一性的序列;
(ii)所述轻链可变区包含SEQ ID NO:8所示的氨基酸序列或者与其具有至少80%序列同一性的序列。
11.根据权利要求9-10中任一项所述的任一抗体或其功能性片段,其中所述抗体是单克隆抗体、嵌合抗体、人源化抗体、单链抗体(scFv)或者双特异性抗体。
12.分离的多核苷酸,其编码根据权利要求9-11中任一项所述的抗体或其功能性片段。
13.分离的多核苷酸的组合,其包括:编码权利要求9-11中任一项所述抗体或其功能性片段之重链的多核苷酸和编码权利要求9-11中任一项所述抗体或其功能性片段之轻链的多核苷酸。
14.表达载体或者表达载体的组合,其包含根据权利要求12的多核苷酸或者根据权利要求13的多核苷酸的组合,所述多核苷酸与允许其所编码的多肽在宿主细胞或无细胞表达系统中表达的调节序列有效连接。
15.药物组合物,其包含权利要求1-8中任一项的缀合物和/或权利要求9-11中任一项的抗体或其功能性片段,以及可药用载体。
16.权利要求1-8中任一项的缀合物、权利要求9-11中任一项的抗体或其功能性片段、权利要求12的多核苷酸、权利要求13的多核苷酸组合、权利要求14的表达载体或权利要求15的药物组合物在制备用于治疗或预防癌症的药物中的用途,优选地所述癌症为间皮素阳性癌症。
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CN201810487856.4A CN110507824A (zh) | 2018-05-21 | 2018-05-21 | 一种抗间皮素抗体及其抗体药物缀合物 |
CN201980002416.8A CN110740754B (zh) | 2018-05-21 | 2019-05-15 | 一种抗间皮素抗体及其抗体药物缀合物 |
JP2020535025A JP2021523874A (ja) | 2018-05-21 | 2019-05-15 | 抗メソセリン抗体およびその抗体薬物コンジュゲート |
AU2019272250A AU2019272250B2 (en) | 2018-05-21 | 2019-05-15 | Anti-mesothelin antibody and antibody-drug conjugate thereof |
KR1020237030872A KR20230135164A (ko) | 2018-05-21 | 2019-05-15 | 항-메소텔린 항체 및 이의 항체 약물 콘쥬게이트 |
PCT/CN2019/086977 WO2019223579A1 (zh) | 2018-05-21 | 2019-05-15 | 一种抗间皮素抗体及其抗体药物缀合物 |
CA3082160A CA3082160C (en) | 2018-05-21 | 2019-05-15 | Anti-mesothelin antibody and antibody drug conjugate thereof |
KR1020207026535A KR20200120728A (ko) | 2018-05-21 | 2019-05-15 | 항-메소텔린 항체 및 이의 항체 약물 콘쥬게이트 |
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BR112020014380-4A BR112020014380A2 (pt) | 2018-05-21 | 2019-05-15 | Anticorpo anti-mesotelina e conjugado de fármaco anticorpo do mesmo |
RU2020113275A RU2747995C1 (ru) | 2018-05-21 | 2019-05-15 | Анти-мезотелин антитело и его конъюгат с лекарственными средствами |
EP19808424.6A EP3695852A4 (en) | 2018-05-21 | 2019-05-15 | ANTI-MESOTHELIN ANTIBODY AND ANTIBODY-ASSOCIATED DRUG CONJUGATE |
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US16/618,110 US20200138968A1 (en) | 2018-05-21 | 2019-05-20 | Process for preparing intermediate of antibody drug conjugate |
EP19807031.0A EP3797795A4 (en) | 2018-05-21 | 2019-05-20 | METHOD FOR PREPARING ANTIBODY-DRUG CONJUGATE INTERMEDIATE |
RU2019142484A RU2724436C1 (ru) | 2018-05-21 | 2019-05-20 | Способ получения промежуточного соединения конъюгата антитело-лекарственное средство |
AU2019268215A AU2019268215B2 (en) | 2018-05-21 | 2019-05-20 | Process for preparing intermediate of antibody drug conjugate |
CN201980002405.XA CN110740753A (zh) | 2018-05-21 | 2019-05-20 | 一种抗体药物偶联物中间体的制备工艺 |
SG11202006515VA SG11202006515VA (en) | 2018-05-21 | 2019-05-20 | Preparation process of antibody drug conjugate intermediate |
JP2020515844A JP6949206B2 (ja) | 2018-05-21 | 2019-05-20 | 抗体薬物複合体中間体の製造方法 |
KR1020207020184A KR102454638B1 (ko) | 2018-05-21 | 2019-05-20 | 항체 약물 접합체 중간체의 제조 방법 |
PCT/CN2019/087641 WO2019223653A1 (zh) | 2018-05-21 | 2019-05-20 | 一种抗体药物偶联物中间体的制备工艺 |
BR112020005596-4A BR112020005596A2 (pt) | 2018-05-21 | 2019-05-20 | processo de preparação de intermediário de conjugado de anticorpo-fármaco |
CA3062265A CA3062265C (en) | 2018-05-21 | 2019-05-20 | Process for preparing intermediate of antibody drug conjugate |
TW108117459A TWI714092B (zh) | 2018-05-21 | 2019-05-21 | 一種抗間皮素抗體及其抗體藥物綴合物 |
JP2023100937A JP2023134472A (ja) | 2018-05-21 | 2023-06-20 | 抗メソセリン抗体およびその抗体薬物コンジュゲート |
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CN111560072A (zh) * | 2020-07-16 | 2020-08-21 | 上海恒润达生生物科技有限公司 | 抗人msln抗体以及靶向msln的免疫效应细胞 |
WO2020233174A1 (zh) * | 2019-05-20 | 2020-11-26 | 烟台迈百瑞国际生物医药有限公司 | 一种抗体药物偶联物中间体的一锅法制备工艺 |
WO2023125813A1 (zh) * | 2021-12-29 | 2023-07-06 | 上海细胞治疗集团有限公司 | 抗间皮素纳米抗体嵌合抗原受体及其应用 |
US11957717B2 (en) | 2020-07-16 | 2024-04-16 | Hrain Biotechnology Co., Ltd. | Anti-human MSLN antibody and MSLN-targeting immune effector cell |
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CN115297889A (zh) * | 2020-09-01 | 2022-11-04 | 荣昌生物制药(烟台)股份有限公司 | 抗c-Met抗体药物偶联物及其应用 |
JP2023169444A (ja) * | 2020-10-01 | 2023-11-30 | 株式会社Epsilon Molecular Engineering | 標的タンパク質と結合し得る架橋ペプチド、当該架橋ペプチドの作製方法、及び当該架橋ペプチドを有効成分とする医薬組成物 |
AU2022248336A1 (en) * | 2021-03-31 | 2023-09-21 | Remegen Co., Ltd. | Preparation and purification method for antibody drug conjugate intermediate |
EP4335873A1 (en) | 2021-05-08 | 2024-03-13 | RemeGen Co., Ltd. | Anti-claudin 18.2 antibody and antibody-drug conjugate thereof |
CN117412991A (zh) * | 2021-06-18 | 2024-01-16 | 南京再明医药有限公司 | 抗人msln人源化抗体及其应用 |
WO2023157989A1 (ko) * | 2022-02-17 | 2023-08-24 | 주식회사 노벨티노빌리티 | 항체-약물 접합체 |
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SG10201700289RA (en) * | 2002-05-02 | 2017-02-27 | Wyeth Corp | Calicheamicin derivative-carrier conjugates |
WO2005117986A2 (en) * | 2004-06-01 | 2005-12-15 | Genentech, Inc. | Antibody drug conjugates and methods |
PT2489364E (pt) * | 2003-11-06 | 2015-04-16 | Seattle Genetics Inc | Compostos de monometilvalina conjugados com anticorpos |
KR20140085544A (ko) * | 2006-05-30 | 2014-07-07 | 제넨테크, 인크. | 항체 및 면역접합체 및 이들의 용도 |
AR076284A1 (es) * | 2009-04-29 | 2011-06-01 | Bayer Schering Pharma Ag | Inmunoconjugados de antimesotelina y usos de los mismos |
CA2819269A1 (en) * | 2010-12-20 | 2012-06-28 | Genentech, Inc. | Anti-mesothelin antibodies and immunoconjugates |
RU2624141C2 (ru) * | 2011-04-01 | 2017-06-30 | ВАЙЕТ ЭлЭлСи | Конъюгаты "антитело-лекарственное средство" |
EP2844300B1 (en) * | 2012-05-01 | 2018-10-17 | Genentech, Inc. | Anti-pmel17 antibodies and immunoconjugates |
CN106279352B (zh) * | 2015-05-29 | 2020-05-22 | 上海新理念生物医药科技有限公司 | 海兔毒素10的衍生物及其应用 |
HUE057906T2 (hu) * | 2015-08-14 | 2022-07-28 | Remegen Biosciences Inc | Kovalens kötõcsoportok ellenanyag-hatóanyag konjugátumokban és eljárások elõállításukra és alkalmazásukra |
US20170281758A1 (en) * | 2016-03-29 | 2017-10-05 | Sorrento Therapeutics, Inc. | Calicheamicin antibody drug conjugates linking an amidoacetyl group to a sugar moiety on calicheamicin |
BR112018070676A2 (pt) * | 2016-04-15 | 2019-02-05 | Zymeworks Inc | construtos de ligação a antígeno multiespecífico que têm como alvo agentes imunoterapêuticos |
JP6727052B2 (ja) * | 2016-07-19 | 2020-07-22 | 株式会社日立製作所 | 生体分子分析用デバイス及び生体分子分析装置 |
CN106938051B (zh) * | 2016-08-22 | 2019-10-11 | 复旦大学 | 靶向于组织因子的抗体-药物偶联物 |
MX2020004100A (es) * | 2017-10-30 | 2020-07-24 | Hoffmann La Roche | Metodo para generacion in vivo de anticuerpos multiespecificos a partir de anticuerpos monoespecificos. |
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2018
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2019
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- 2019-05-15 EP EP19808424.6A patent/EP3695852A4/en active Pending
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- 2019-05-15 KR KR1020207026535A patent/KR20200120728A/ko not_active IP Right Cessation
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- 2019-05-15 BR BR112020014380-4A patent/BR112020014380A2/pt unknown
- 2019-05-15 CN CN201980002416.8A patent/CN110740754B/zh active Active
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- 2019-05-20 JP JP2020515844A patent/JP6949206B2/ja active Active
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- 2019-05-21 TW TW108117459A patent/TWI714092B/zh active
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WO2020233174A1 (zh) * | 2019-05-20 | 2020-11-26 | 烟台迈百瑞国际生物医药有限公司 | 一种抗体药物偶联物中间体的一锅法制备工艺 |
US11717575B2 (en) | 2019-05-20 | 2023-08-08 | Mabplex International Co., Ltd. | One-pot process for preparing intermediate of antibody-drug conjugate |
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WO2022012097A1 (zh) * | 2020-07-16 | 2022-01-20 | 上海恒润达生生物科技股份有限公司 | 抗人msln抗体以及靶向msln的免疫效应细胞 |
US11957717B2 (en) | 2020-07-16 | 2024-04-16 | Hrain Biotechnology Co., Ltd. | Anti-human MSLN antibody and MSLN-targeting immune effector cell |
WO2023125813A1 (zh) * | 2021-12-29 | 2023-07-06 | 上海细胞治疗集团有限公司 | 抗间皮素纳米抗体嵌合抗原受体及其应用 |
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