Anti-CD20 multivalent HPMA copolymer-Fab' conjugates for the direct induction of apoptosis.
Anti-CD20 multivalent HPMA copolymer-Fab' conjugates for the direct induction of apoptosis.
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DOI：
10.1016/j.biomaterials.2012.06.024
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发表时间：
2012-10
期刊：
影响因子：
14
通讯作者：
Kopecek, Jindrich
中科院分区：
文献类型：
--
作者：
Chu, Te-Wei;Yang, Jiyuan;Kopecek, Jindrich
采用可逆加成-断裂链转移（RAFT）聚合法合成了一种高分子量线性共聚物--N-（2-羟丙基）甲基丙烯酰胺（HPMA）接枝抗CD 20单克隆抗体（mAb）Fab ′片段的复合仿生体系。将人非霍奇金淋巴瘤（NHL）Raji B细胞暴露于多价缀合物导致CD 20受体交联并开始凋亡。合成了具有不同分子量和化合价（每个聚合物链的Fab′的量）的五种缀合物。其中一种共聚物在主链中含有酶可降解肽序列（GFLG）。与未缀合的全mAb相比，多价性导致更高的亲合力和凋亡诱导。时间依赖性研究表明，在较短的暴露时间内，缀合物的细胞毒性比与二级抗体超交联的mAb表现出更慢的起效;然而，在较长的时间间隔内，HPMA共聚物缀合物实现了显著更高的生物学功效。此外，共轭物的结构和Raji B细胞凋亡之间的关系的研究表明，化合价和聚合物的分子量影响生物活性，而插入到骨架的肽序列在体外不是一个因素。
A hybrid biomimetic system comprising high-molecular-weight, linear copolymer of N-(2-hydroxypropyl)methacrylamide (HPMA) grafted with multiple Fab′ fragments of anti-CD20 monoclonal antibody (mAb) was synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization followed by attachment of Fab′ fragments via thioether bonds. Exposure of human non-Hodgkin’s lymphoma (NHL) Raji B cells to the multivalent conjugates resulted in crosslinking of CD20 receptors and commencement of apoptosis. Five conjugates with varying molecular weight and valence (amount of Fab′ per polymer chain) were synthesized. One of the copolymers contained enzyme degradable peptide sequences (GFLG) in the backbone. The multivalency led to higher avidity and apoptosis induction compared to unconjugated whole mAb. Time-dependent studies showed that the cytotoxicity of conjugates exhibited a slower onset at shorter exposure times than mAb hyper-crosslinked with a secondary Ab; however, at longer time intervals the HPMA copolymer conjugates achieved significantly higher biological efficacies. In addition, study of the relationship between the structure of conjugates and Raji B cell apoptosis revealed that both valency and polymer molecular weight influenced biological activities, while insertion of peptide sequences into the backbone was not a factor in vitro.
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影响因子：
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