Exatecan mesylate: a novel topoisomerase I inhibitor in ADC technolog

Exatecan mesylate: a novel topoisomerase I inhibitor in ADC technolog

Antibody-drug conjugates (ADCs) are promising drugs. Compared with conventional chemotherapy drugs, they have a wider therapeutic index (TI) because they can effectively and specifically deliver drugs to tumor cells expressing antigens.

Exatecan mesylate (DX-8951f), a semisynthetic water-soluble derivative of camptothecin, is a new type of topoisomerase I inhibitor with anti-tumor activity and is suitable for a variety of xenograft models (including in vivo CPT-11-drug-resistant tumor) with a stronger potency.

Exatecan mesylate can inhibit the activity of topoisomerase I by stabilizing the cleavable complex between topoisomerase I and DNA and inhibiting the connection of DNA breaks, thereby inhibiting DNA replication and triggering apoptotic cells death. This drug does not require enzymatic activation and is more potent than camptothecin and other camptothecin analogs.

Structures of Exatecan mesylate and DXd Figure 1. Structures of Exatecan mesylate and DXd (Ogitani, Y., 2016).

The scientists developed a novel payload linker technology by using the anti-HER2 antibody trastuzumab and exatecan derivatives (DX-8951 derivatives, DXds). Trastuzumab and DXds are joined together through maleimidohexanoylhexosyl glycidyl bonds. After the reduction of the interchain disulfide bond of the antibody, β-glycyl-phenylpropanine is formed through a cysteine residue Aminoacyl-glycine (GGFG) peptide linker. The peptide linker is designed to be cleaved by lysosomal enzymes and subsequently release DXd. Testing showed that after intravenous injection of ADC into HER2-positive KPL-4 tumor-bearing mice, DXd was mainly released in the tumor as designed. The anti-HER2-DXd ADC showed anti-tumor activity in vitro and in vivo, indicating the importance of this new technology.

Structures of DXd-ADCFigure 2. Structures of DXd-ADC (Ogitani, Y., 2016).

In this study, scientists applied the topoisomerase I inhibitor DXd to a variety of antibodies (including those that have been validated by ADC, such as anti-CD30, CD33, and CD70 antibodies), all of which demonstrated the versatility of the new payload. The results showed that the DXd payload has about 10 times stronger topoisomerase inhibitory activity than SN-38. In addition, DXd ADC has a stable linker part, designed to be cleaved by lysosomal enzymes, which should have a specific payload release capacity in the cell. These improvements may result in a larger TI in the DXd ADC than that in the SN-38 ADC.

In summary, these findings indicate that this new technology with low bone marrow toxicity potential can be widely used in the ADC field and provide additional payload linker options for traditional technologies.


  1. Ogitani, Y., Abe, Y., Iguchi, T., Yamaguchi, J., Terauchi, T., Kitamura, M., … Agatsuma, T. Wide application of a novel topoisomerase I inhibitor-based drug conjugation technology. Bioorganic & Medicinal Chemistry Letters. 2016; 26(20):5069-5072.
  2. Sunil Sharma, Nancy Kemeny, Gary K. Schwartz, et al. Phase I Study of Topoisomerase I Inhibitor Exatecan Mesylate (DX-8951f) Given as Weekly 24-Hour Infusions Three of Every Four Weeks. Clinical Cancer Research. 2001; 7(12): 3963-3970.
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