What is a DXd drug and how does this technology revolutionize cancer treatment?

October 7, 2025 •

3 min read

Over two decades, antibody-drug conjugates (ADCs) have transformed targeted cancer therapy, and the next-generation platform using a DXd drug as a payload is at the forefront of this innovation. This technology, pioneered by Daiichi Sankyo, is built around a potent topoisomerase I inhibitor, designed to precisely deliver chemotherapy to cancer cells while minimizing systemic harm.

Quick Summary

A DXd drug, an exatecan derivative, is the cytotoxic payload in advanced antibody-drug conjugates (ADCs) that uses a stable, cleavable linker system. It functions by inhibiting topoisomerase I within cancer cells, causing DNA damage and cell death, including a unique bystander killing effect on neighboring cells. Key examples include trastuzumab deruxtecan (Enhertu) and datopotamab deruxtecan (Datroway).

Key Points

DXd is the Cytotoxic Payload: A DXd drug refers to a highly potent topoisomerase I inhibitor payload, derived from exatecan, used in advanced antibody-drug conjugates (ADCs).
Targeted Delivery System: DXd payloads are linked to monoclonal antibodies that recognize and deliver the drug to specific antigens on cancer cells, minimizing harm to healthy tissues.
Unique Bystander Effect: The membrane-permeable nature of the released DXd payload allows it to diffuse into and kill neighboring cancer cells that may lack the target antigen, addressing tumor heterogeneity.
High Drug-to-Antibody Ratio (DAR): DXd-based ADCs often feature a high DAR, delivering a more concentrated dose of chemotherapy to the tumor site for enhanced efficacy.
Stable and Cleavable Linker: The linker connecting the antibody and payload is designed for stability in the bloodstream, with specific cleavage triggered by enzymes inside tumor cells to ensure controlled release.
Clinical Success: Examples like trastuzumab deruxtecan (Enhertu®) and datopotamab deruxtecan (Datroway®) have demonstrated significant clinical efficacy in various HER2-positive, HER2-low, and TROP2-positive cancers.

What are antibody-drug conjugates (ADCs)?

Antibody-drug conjugates (ADCs) are a powerful class of biopharmaceuticals used in targeted cancer therapy. They consist of a monoclonal antibody that targets specific cancer cells, a potent chemotherapy drug (payload), and a chemical linker connecting the two. The linker's stability ensures the payload is released primarily at the tumor site.

The Anatomy of a DXd-Based ADC

A DXd drug is the potent payload in a new generation of ADCs developed by Daiichi Sankyo. 'DXd' is a derivative of exatecan, a strong topoisomerase I inhibitor. DXd-based ADCs are designed for enhanced efficacy through their specific components:

The DXd Payload: This potent topoisomerase I inhibitor disrupts DNA processes in rapidly dividing cells, leading to DNA damage and apoptosis (cell death). Its potency is greater than older ADC payloads.
The Cleavable Linker: A stable tetrapeptide-based linker connects the payload to the antibody. It is designed to be cleaved by enzymes found within tumor cells, ensuring controlled release of the DXd payload.
High Drug-to-Antibody Ratio (DAR): DXd-based ADCs often have a high DAR, delivering more payload molecules per antibody and increasing the drug concentration at the tumor.

How DXd Drugs Work: A Dual-Action Mechanism

DXd-based ADCs utilize a dual mechanism, including a bystander effect, to target and kill cancer cells.

Mechanism of Action:

The antibody binds to a specific antigen on cancer cells.
The ADC is internalized into the cell.
Within the cell, enzymes cleave the linker, releasing the active DXd payload.
DXd inhibits topoisomerase I in the cell's nucleus, causing DNA damage and cell death.

The Bystander Effect: The released DXd payload is membrane-permeable and can kill nearby cancer cells that do not express the target antigen. This is effective against tumors with varied antigen expression.

Key Examples of DXd Drugs in Clinical Practice

Several DXd-based ADCs have been approved or are in development:

Trastuzumab deruxtecan (Enhertu®): Targets HER2 and is used for HER2-positive and HER2-low breast, gastric, and lung cancers.
Datopotamab deruxtecan (Datroway®): Targets TROP2 and is approved for certain metastatic breast cancers, with trials in other solid tumors.
Patritumab deruxtecan (HER3-DXd): An investigational ADC targeting HER3 for EGFR-mutant non-small cell lung cancer.

The Clinical Impact of DXd Drugs

DXd-based ADCs offer significant clinical benefits:

Enhanced Efficacy: Their potency and bystander effect can lead to strong and lasting responses.
Treatment of Low-Expression Tumors: The bystander effect allows efficacy in tumors with low target antigen levels, expanding treatment options.
Overcoming Resistance: By using a different mechanism (topoisomerase I inhibition), DXd drugs can be effective in tumors resistant to other treatments.

Comparison of DXd-Based ADCs vs. Traditional Chemotherapy


Feature	DXd-Based ADCs	Traditional Chemotherapy
Targeting Mechanism	High specificity via monoclonal antibody.	Non-specific distribution throughout the body.
Toxicity	Lower systemic toxicity due to targeted delivery; specific risks like ILD and eye problems.	High systemic toxicity, affecting healthy, rapidly dividing cells (e.g., hair, bone marrow, GI tract).
Mechanism	Inhibits topoisomerase I specifically in or near cancer cells.	Various mechanisms, such as DNA alkylation or microtubule inhibition.
Bystander Effect	Present and potent due to the membrane-permeable payload.	Not applicable; acts systemically and non- selectively.
Therapeutic Index	Often higher in selected patient populations.	Narrower margin between efficacy and toxicity.
Clinical Application	Treats tumors with specific antigen expression (e.g., HER2-low).	Broad-spectrum use, but with more severe systemic side effects.

Conclusion: The Future of Targeted Oncology

A DXd drug represents a major advancement in ADC technology, providing a potent and versatile platform for targeted cancer treatment. By combining a powerful topoisomerase I inhibitor payload, a stable cleavable linker, and a specific antibody, DXd-based ADCs deliver chemotherapy precisely. Their bystander effect helps overcome tumor heterogeneity, broadening effective treatment to include tumors with low target antigen expression. Drugs like trastuzumab deruxtecan and datopotamab deruxtecan showcase this technology's success in treating various advanced cancers. Ongoing research in DXd-based ADCs holds significant promise for improving outcomes and providing new hope to patients. These therapies are becoming a key element of modern oncology, offering more effective, personalized treatment.

For further information on ADCs and DXd technology, explore publications by Daiichi Sankyo and AstraZeneca, the joint developers of some key drugs like Enhertu® and Datroway®.

Frequently Asked Questions

The abbreviation DXd stands for deruxtecan, which is an exatecan derivative and a highly potent topoisomerase I inhibitor used as the cytotoxic payload in a new generation of antibody-drug conjugates (ADCs).

DXd drugs work by inhibiting topoisomerase I, a key enzyme involved in DNA replication. This inhibition causes irreparable DNA damage in rapidly dividing cancer cells, ultimately triggering programmed cell death (apoptosis).

The bystander effect is the ability of a released DXd payload to diffuse out of the targeted cancer cell and kill nearby tumor cells that may have low or no expression of the target antigen. This helps overcome tumor heterogeneity.

DXd-based ADCs differ from older ADCs due to their potent, membrane-permeable payload (DXd), a stable and cleavable linker system, and a high drug-to-antibody ratio. These features contribute to a powerful bystander effect and enhanced efficacy.

Examples include trastuzumab deruxtecan (Enhertu®), which targets HER2, and datopotamab deruxtecan (Datroway®), which targets TROP2. Both have received regulatory approval for specific cancer indications.

Common side effects can include nausea, fatigue, hair loss, and low blood counts. More serious side effects can occur, such as interstitial lung disease (ILD) and severe eye problems, which require close monitoring.

Yes. Due to the unique bystander effect of its DXd payload, trastuzumab deruxtecan (T-DXd) is effective in treating tumors with low levels of HER2 expression, significantly expanding the treatment options for these patients.