Enhertu, a fascinating FDA-approved antibody-drug conjugate (ADC) jointly brought to market by Daiichi Sankyo and AstraZeneca, is prominently known as DS-8201 (T-DXd) or Trastuzumab Deruxtecan. It is prescribed for adults with HER2-low breast cancer that is inoperable or has metastasized, and who have previously undergone chemotherapy.
Enhertu represents the third generation of ADC drugs. Its revolutionary site-specific conjugation technology ensures a consistently high drug-to-antibody ratio (DAR) of approximately eight cytotoxic agents per antibody. This unique attribute significantly enhances its efficacy, particularly against cancer cells with low antigen expression, thanks to the bystander effect it can induce. This load of 8 cytotoxic agents per antibody maintains uniformity and remains stable in the bloodstream, thanks to the tetrapeptide linker. Importantly, these payloads can be selectively released by enzymes that are upregulated in tumor cells, enabling targeted localized drug delivery. In contrast, typical ADCs on the market tend to carry a variable number of cytotoxic agents, typically ranging from 2 to 5. The high DAR of Enhertu positions its efficacy as two to four times higher than previously approved ADC drugs.
Figure 1: Enhertu with cleavable tetrapeptide linker attaching antibody to payload
Enhertu is comprised of a HER2 monoclonal antibody, trastuzumab, a topoisomerase I inhibitor that is an exatecan derivative (DXd or Deruxtecan), and a cleavable tetrapeptide-based linker Mal-Gly-Gly-L-Phe-N-[(carboxymethoxy)methyl]Glycinamide. The ADC was built up as described in Figure 2 below.
Figure 2: Synthesis of Enhertu
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Nakada T, Sugihara K, Jikoh T, Abe Y, Agatsuma T. The Latest Research and Development into the Antibody-Drug Conjugate, [fam-] Trastuzumab Deruxtecan (DS-8201a), for HER2 Cancer Therapy. Chem Pharm Bull (Tokyo). 2019;67(3):173-185. doi: 10.1248/cpb.c18-00744. PMID: 30827997.