Trastuzumab Deruxtecan
[CAS# 1826843-81-5]

Identification

• Classification: Biochemical >> Inhibitor >> DNA damage >> Topoisomerase inhibitor
• Name: Trastuzumab Deruxtecan
• Synonyms: DS-8201
• Molecular Weight: 145000
• CAS Registry Number: 1826843-81-5

Discovory and Applicatios

Trastuzumab deruxtecan is an antibody-drug conjugate (ADC) that was developed through the integration of monoclonal antibody and cytotoxic chemotherapy technologies. It is composed of three main parts: a humanized anti-HER2 IgG1 monoclonal antibody (trastuzumab), a cleavable tetrapeptide-based linker, and a topoisomerase I inhibitor payload (deruxtecan). This structure allows for targeted delivery of the cytotoxic agent specifically to HER2-expressing cancer cells, minimizing systemic toxicity and enhancing antitumor efficacy.

The discovery of trastuzumab deruxtecan built upon earlier work on HER2-targeted therapies. HER2 (human epidermal growth factor receptor 2) is a transmembrane receptor tyrosine kinase that is overexpressed in a variety of cancers, including breast, gastric, and lung cancers. The original monoclonal antibody, trastuzumab, was developed in the 1990s to bind to HER2 and inhibit downstream signaling pathways that promote tumor cell proliferation and survival. Trastuzumab also induces antibody-dependent cellular cytotoxicity. While trastuzumab alone showed clinical benefit in HER2-positive cancers, many patients experienced resistance or relapse, prompting the search for more potent therapeutic strategies.

Trastuzumab deruxtecan was designed to overcome resistance mechanisms by combining the specificity of trastuzumab with a highly potent chemotherapeutic payload. The cytotoxic component, deruxtecan, is a derivative of exatecan, a topoisomerase I inhibitor that interferes with DNA replication and transcription, leading to cell death. This payload is linked to the antibody via a cleavable linker that is stable in plasma but cleaved by lysosomal enzymes after internalization into the cancer cell. Once the conjugate is internalized by HER2-expressing cells, the linker is degraded, releasing the active cytotoxic drug inside the cell.

The compound is characterized by a high drug-to-antibody ratio (DAR), approximately eight molecules of deruxtecan per antibody. This higher DAR increases the delivery of cytotoxic payload to tumor cells while maintaining pharmacokinetic stability. Trastuzumab deruxtecan also exhibits a bystander effect, wherein the released payload diffuses into neighboring tumor cells, including those with low HER2 expression, thereby enhancing its therapeutic effect.

Trastuzumab deruxtecan has been approved for clinical use in multiple countries for the treatment of HER2-positive breast cancer, HER2-positive gastric or gastroesophageal junction adenocarcinoma, and HER2-mutant non-small cell lung cancer. Clinical trials have demonstrated its efficacy in patients who had previously received multiple lines of HER2-targeted therapy, including trastuzumab and trastuzumab emtansine. The drug has shown significant tumor shrinkage and prolonged progression-free survival in several studies.

In addition to its approved indications, trastuzumab deruxtecan is being investigated in ongoing clinical trials for other HER2-expressing or HER2-mutant tumors, including colorectal, biliary tract, and endometrial cancers. Its activity in tumors with varying levels of HER2 expression has led to interest in its potential utility beyond traditional HER2-positive classifications.

Despite its clinical benefits, trastuzumab deruxtecan is associated with specific adverse effects. The most notable is interstitial lung disease (ILD), which has been observed in a small percentage of treated patients and can be serious or even fatal if not promptly recognized and managed. Other common adverse effects include nausea, fatigue, alopecia, and myelosuppression. As a result, patients receiving this therapy require close monitoring, and treatment guidelines have been established to manage ILD and other toxicities.

The development of trastuzumab deruxtecan represents a significant advancement in the field of targeted cancer therapy, demonstrating the potential of antibody-drug conjugates to improve outcomes in patients with refractory or advanced cancers. Its success has further validated the concept of combining targeted biologics with potent cytotoxic agents and has influenced the design of other ADCs currently under development.