Mechanism of Action

ENHERTU is a specifically engineered HER2-directed antibody–drug
conjugate (ADC)1,2

HER2-directed mAb: provides targeted delivery of cytotoxic agent and consists of the same amino acid sequence as trastuzumab. Topoisomerase 1 inhibitor payload: Highly potent payload is an exatecan derivative, known as DXd, with a short systemic half-life; upon release, membrane-permeable payload causes DNA damage and cell death. Tumor-selective cleavable linker: attaches payload to the antibody; linker-payload is table in plasma; linker selectively cleaved by enzymes that are upregulated in tumor cells

HER2-directed mAb1

  • Provides targeted delivery of cytotoxic agent1,2
  • Consists of the same amino acid sequence as trastuzumab3

Topoisomerase I inhibitor payload1,2,a

  • Highly potent payload is an exatecan derivative, known as DXd, with a short systemic half-life1,3
  • Upon release, membrane-permeable payload causes DNA damage and cell death, resulting in destruction of targeted tumor cells and surrounding cells, known as the bystander antitumor effect1,3,4

Tumor-selective cleavable linker1-3,a

  • Attaches payload to the antibody1
  • Linker-payload is stable in plasma2,3
  • Linker selectively cleaved by enzymes that are upregulated in tumor cells1,3
HER2-directed mAb: provides targeted delivery of cytotoxic agent and consists of the same amino acid sequence as trastuzumab. Topoisomerase 1 inhibitor payload: Highly potent payload is an exatecan derivative, known as DXd, with a short systemic half-life; upon release, membrane-permeable payload causes DNA damage and cell death. Tumor-selective cleavable linker: attaches payload to the antibody; linker-payload is table in plasma; linker selectively cleaved by enzymes that are upregulated in tumor cells

ENHERTU has a homogeneous and high drug-to-antibody ratio of
~8 molecules of cytotoxic agent per antibody1-3,a,b

aBased on in vitro and in vivo non-clinical studies. The clinical relevance of these features is under investigation.

bADCs are a mixture of molecules in which the DAR is variable. Homogeneity of DAR refers to a mixture where there is low variability of DAR; the payload number per antibody falls into a narrow range.3

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DAR, drug-to-antibody ratio; DNA, deoxyribonucleic acid; HER2, human epidermal growth factor receptor 2; mAb, monoclonal antibody.