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Specific Conjugation of the Hinge Region for Homogeneous Preparation of Antibody Fragment-Drug Conjugate: A Case Study for Doxorubicin-PEG-anti-CD20 Fab' Synthesis
Zhou, Zhan1,2; Zhang, Jing1; Zhang, Yan1; Ma, Guanghui1; Su, Zhiguo1
2016
发表期刊BIOCONJUGATE CHEMISTRY
ISSN1043-1802
卷号27期号:1页码:238-246
摘要Conventional preparation strategies for antibody-drug conjugates (ADCs) result in heterogeneous products with various molecular sizes and species. In this study, we developed a homogeneous preparation strategy by site-specific conjugation of the anticancer drug with an antibody fragment. The model drug doxorubicin (DOX) was coupled to the Fab' fragment of anti-CD20 IgG at its permissive sites through a heterotelechelic PEG linker, generating an antibody fragment-drug conjugate (AFDC). Anti-CD20 IgG was digested and reduced specifically with beta-mercaptoethylamine to generate the Fab' fragment with two free mercapto groups in its hinge region. Meanwhile, DOX was conjugated with alpha-succinimidylsuccinate omega-maleimide polyethylene glycol (NHS-PEG-MAL) to form MAL-PEG-DOX, which was subsequently linked to the free mercapto containing Fab' fragment to form a Fab'-PEG-DOX conjugate. The dual site-specific bioconjugation was achieved through the combination of highly selective reduction of IgG and introduction of heterotelechelic PEG linker. The resulting AFDC provides an utterly homogeneous product, with a definite ratio of one fragment to two drugs. Laser confocal microscopy and cell ELISA revealed that the AFDC could accumulate in the antigen-positive Daudi tumor cell. In addition, the Fab'-PEG-DOX retained appreciable targeting ability and improved antitumor activity, demonstrating an excellent therapeutic effect on the lymphoma mice model for better cure rate and significantly reduced side effects.
文章类型Article
WOS标题词Science & Technology ; Life Sciences & Biomedicine ; Physical Sciences
DOI10.1021/acs.bioconjchem.5b00626
收录类别SCI
语种英语
关键词[WOS]MONOCLONAL-ANTIBODY ; THERAPEUTIC INDEX ; CANCER-THERAPY ; DOXORUBICIN ; EXPRESSION ; ANTI-CD20 ; GROWTH ; POTENT ; CELLS
WOS研究方向Biochemistry & Molecular Biology ; Chemistry
WOS类目Biochemical Research Methods ; Biochemistry & Molecular Biology ; Chemistry, Multidisciplinary ; Chemistry, Organic
项目资助者National Natural Science Foundation of China(21106163 ; Science and Technology Service Network Initiative(KFJ-EW-STS-027) ; National High Technology Research and Development Program of China (863 Program)(2012AA021202 ; National Key Basic Research Program of China (973 Program)(2013CB733600) ; National Key Foundation for Exploring Scientific Instrument of China(2013YQ14040508) ; 21306207 ; 2012AA02A406 ; 21336010) ; 2014AA021006)
WOS记录号WOS:000368651600026
引用统计
文献类型期刊论文
条目标识符http://ir.ipe.ac.cn/handle/122111/20598
专题生化工程国家重点实验室
作者单位1.Chinese Acad Sci, Inst Proc Engn, Natl Key Lab Biochem Engn, 1 Beierjie St, Beijing 100190, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714
Zhou, Zhan,Zhang, Jing,Zhang, Yan,et al. Specific Conjugation of the Hinge Region for Homogeneous Preparation of Antibody Fragment-Drug Conjugate: A Case Study for Doxorubicin-PEG-anti-CD20 Fab' Synthesis[J]. BIOCONJUGATE CHEMISTRY,2016,27(1):238-246.
APA Zhou, Zhan,Zhang, Jing,Zhang, Yan,Ma, Guanghui,&Su, Zhiguo.(2016).Specific Conjugation of the Hinge Region for Homogeneous Preparation of Antibody Fragment-Drug Conjugate: A Case Study for Doxorubicin-PEG-anti-CD20 Fab' Synthesis.BIOCONJUGATE CHEMISTRY,27(1),238-246.
MLA Zhou, Zhan,et al."Specific Conjugation of the Hinge Region for Homogeneous Preparation of Antibody Fragment-Drug Conjugate: A Case Study for Doxorubicin-PEG-anti-CD20 Fab' Synthesis".BIOCONJUGATE CHEMISTRY 27.1(2016):238-246.
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