An antibody-drug conjugate (ADC) is a targeted therapy that delivers a potent chemotherapy drug directly to cancer cells, aiming to spare healthy cells. This approach combines the precise targeting ability of antibodies with the cell-killing power of chemotherapy. The goal is to create a more effective treatment with fewer side effects compared to traditional, non-targeted chemotherapy.
How Antibody-Drug Conjugates Work
An antibody-drug conjugate has three distinct components. The first is a monoclonal antibody, a lab-made protein that acts as a guidance system. This antibody is engineered to recognize and bind to a specific protein, an antigen, that is abundant on the surface of cancer cells but less common on healthy cells.
Connected to the antibody is the second component: the cytotoxic payload. This is a powerful chemotherapy drug capable of killing the cancer cell once inside. The antibody and payload are joined by the third component, a chemical linker. This linker is designed to be stable while the ADC circulates in the bloodstream, preventing the premature release of the drug.
The process begins when the ADC is administered and travels through the bloodstream. When the antibody encounters a cancer cell expressing the target antigen, it binds to the cell’s surface. This binding triggers internalization, where the cancer cell absorbs the ADC. Once inside the cell, the linker is broken down, releasing the cytotoxic payload to destroy the cancer cell.
ADCs Used in Breast Cancer
One of the most well-known ADCs is Enhertu (trastuzumab deruxtecan), which targets the human epidermal growth factor receptor 2 (HER2). It is approved for patients with HER2-positive breast cancer and for those with HER2-low breast cancer. This is a newer classification where cancer cells have some HER2 proteins but not enough to be considered HER2-positive, expanding treatment options.
Another ADC targeting the HER2 protein is Kadcyla (ado-trastuzumab emtansine). Kadcyla combines the same HER2-targeting antibody, trastuzumab, with a different chemotherapy payload called emtansine. It is a standard treatment for patients with HER2-positive breast cancer, often used after other targeted therapies have been tried.
For Triple-Negative Breast Cancer (TNBC), which lacks HER2 and hormone receptors, Trodelvy (sacituzumab govitecan) is a standard of care. It works by targeting a protein called Trop-2, which is commonly found on the surface of TNBC cells. By targeting Trop-2, Trodelvy delivers its payload to these difficult-to-treat cancer cells, providing a targeted option for patients.
ADCs Used in Blood Cancers
The application of antibody-drug conjugates extends into the treatment of hematologic malignancies, or blood cancers. For certain types of lymphoma, Adcetris (brentuximab vedotin) is an example. It targets the CD30 antigen, a protein found on the surface of cancer cells in Hodgkin lymphoma and some non-Hodgkin lymphomas, delivering a drug to disrupt cell division.
In cases of diffuse large B-cell lymphoma (DLBCL), a common type of non-Hodgkin lymphoma, Polivy (polatuzumab vedotin) is utilized. This ADC is designed to bind to the CD79b protein, which is prevalent on the surface of B-cells. By targeting CD79b, Polivy delivers its cytotoxic payload to the malignant B-cells.
Other blood cancers are also treated with ADCs. For acute lymphoblastic leukemia (ALL), Besponsa (inotuzumab ozogamicin) targets the CD22 antigen on cancerous B-cells. In the treatment of multiple myeloma, Blenrep (belantamab mafodotin) targets the B-cell maturation antigen (BCMA), which is highly expressed on myeloma cells.
ADCs Used in Other Solid Tumors
The use of antibody-drug conjugates has expanded to other solid tumors. In the treatment of urothelial cancer, which includes bladder cancer, Padcev (enfortumab vedotin) has become a therapy. This ADC targets Nectin-4, a protein highly expressed on the surface of urothelial cancer cells.
Enhertu, known for its use in breast cancer, is also approved for certain types of non-small cell lung cancer (NSCLC) with a specific HER2 mutation. For patients with recurrent or metastatic cervical cancer, Tivdak (tisotumab vedotin) offers a targeted approach. It works by seeking out a protein called Tissue Factor, which is often present on the surface of cervical cancer cells.
The list of cancers treatable with ADCs continues to grow. Trodelvy, for example, has also gained approval for use in urothelial cancer, showcasing how a single ADC can be effective across different tumor types that share the same surface antigen. This expanding field of research is continually uncovering new applications for this form of therapy.