文章基本信息

标题：Chemotherapy payload of anti-insoluble fibrin antibody-drug conjugate is released specifically upon binding to fibrin
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作者：Hirobumi Fuchigami ; Shino Manabe ; Masahiro Yasunaga 等
期刊名称：Scientific Reports
电子版ISSN：2045-2322
出版年度：2018
卷号：8
期号：1
页码：14211
DOI：10.1038/s41598-018-32601-0
语种：English
出版社：Springer Nature
摘要：Cancer-induced blood coagulation in human tumour generates insoluble fibrin (IF)-rich cancer stroma in which uneven monoclonal antibody (mAb) distribution reduce the potential effectiveness of mAb-mediated treatments. Previously, we developed a mAb that reacts only with IF and not with fibrinogen (FNG) or the fibrin degradation product (FDP). Although IF, FNG and FDP share same amino acid sequences, the mAb is hardly neutralised by FNG and FDP in circulation and accumulates in fibrin clots within tumour tissue. Here, we created an antibody drug conjugate (ADC) using the anti-IF mAb conjugated with a chemotherapy payload (IF-ADC). The conjugate contains a linker severed specifically by plasmin (PLM), which is activated only on binding to IF. Imaging mass spectrometry showed the substantial intratumour distribution of the payload following the IF-ADC injection into mice bearing IF-rich 5–11 xenografts derived from pancreatic tumours of LSL-Kras ^G12D/+; LSL-Trp53 ^R172H/+; Ptf1a-Cre (KPC) mice. IF-ADC treatment significantly extended the survival of the KPC mice. These data suggest that conjugating chemotherapy drugs to this IF-specific mAb could represent an effective means of treating stroma-rich tumours