2. Academic Validation
  3. Chemotherapy payload of anti-insoluble fibrin antibody-drug conjugate is released specifically upon binding to fibrin

Chemotherapy payload of anti-insoluble fibrin antibody-drug conjugate is released specifically upon binding to fibrin

  • Sci Rep. 2018 Sep 21;8(1):14211. doi: 10.1038/s41598-018-32601-0.
Hirobumi Fuchigami 1 2,  Shino Manabe 3,  Masahiro Yasunaga 1 2,  Yasuhiro Matsumura 4 5
Affiliations

Affiliations

  • 1 Division of Developmental Therapeutics, Exploratory Oncology Research & Clinical Trial Centre, National Cancer Centre, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
  • 2 Department of Integrated Bioscience, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba, 277-8561, Japan.
  • 3 Synthetic Cellular Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan.
  • 4 Division of Developmental Therapeutics, Exploratory Oncology Research & Clinical Trial Centre, National Cancer Centre, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. yhmatsum@east.ncc.go.jp.
  • 5 Department of Integrated Bioscience, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba, 277-8561, Japan. yhmatsum@east.ncc.go.jp.
PMID: 30242282 DOI: 10.1038/s41598-018-32601-0
Abstract

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-KrasG12D/+; LSL-Trp53R172H/+; 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.

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