Antibody-drug conjugates (ADCs) are an innovative class of targeted therapies that deliver potent anti-cancer drugs directly to tumor cells. They combine the specificity of antibodies with the cell-killing power of chemotherapy. This approach maximizes therapeutic effects on cancer cells while minimizing harm to healthy tissues. ADCs represent a significant advancement in precision oncology, offering a new strategy for combating various malignancies.
Understanding HER2
HER2, or Human Epidermal Growth Factor Receptor 2, is a protein found on the surface of human cells. In healthy cells, HER2 regulates cell growth, division, and repair. It is part of a family of receptors that transmit signals inside the cell to promote these normal functions.
However, in some cancers, the gene responsible for making HER2 can have extra copies, a condition known as HER2 gene amplification, or the cells can produce too many HER2 receptors, which is called HER2 overexpression. This excessive amount of HER2 on the cell surface leads to uncontrolled signaling, causing cells to divide rapidly and uncontrollably. This uncontrolled cell growth can drive tumor development and progression, making HER2 an important target for cancer therapies.
How HER2 Antibody-Drug Conjugates Work
HER2 antibody-drug conjugates (ADCs) are designed to deliver a potent chemotherapy drug directly to cancer cells that display the HER2 protein. Each ADC consists of three main components. First, a monoclonal antibody is engineered to specifically recognize and bind to the HER2 protein on the surface of cancer cells.
Second, a cytotoxic payload, a powerful chemotherapy drug, is attached to the antibody. This payload is selected for its ability to kill cancer cells effectively. The third component is a chemical linker that securely connects the antibody to the cytotoxic payload, ensuring the drug remains inactive until it reaches its target.
Once administered, the antibody portion of the ADC binds to HER2 receptors on the cancer cell surface. This binding triggers receptor-mediated endocytosis, where the entire antibody-drug complex is internalized into the cancer cell within an endosome. Inside the cell, typically within lysosomes, the linker is cleaved, releasing the active cytotoxic payload. The liberated drug then acts within the cancer cell, often by damaging its DNA or disrupting its internal structures, leading to programmed cell death while sparing many healthy cells.
Applications in Cancer Treatment
HER2 antibody-drug conjugates are primarily used in the treatment of cancers that overexpress the HER2 protein. A major application is in HER2-positive breast cancer, where 15-30% of cases exhibit HER2 amplification or overexpression. These therapies have significantly improved outcomes for patients with this aggressive subtype of breast cancer.
Beyond breast cancer, HER2 ADCs have also shown efficacy in other malignancies. These include gastric and gastroesophageal junction cancers, where HER2 overexpression is found in 10-30% of cases. The presence of HER2 overexpression or amplification is a key factor that determines a patient’s eligibility for these targeted treatments.
Key HER2 Antibody-Drug Conjugates
Several HER2 antibody-drug conjugates have received regulatory approval for cancer treatment. Trastuzumab emtansine (T-DM1), marketed as Kadcyla, was among the first in this class to be approved. T-DM1 combines the HER2-targeting antibody trastuzumab with the chemotherapy drug emtansine.
Another ADC is trastuzumab deruxtecan (T-DXd), known by the brand name Enhertu. This ADC also uses the trastuzumab antibody but is linked to a different chemotherapy payload, deruxtecan, a topoisomerase 1 inhibitor. T-DXd has received approval for HER2-positive breast cancer, including those with low HER2 expression, and has also been approved for HER2-positive solid tumors regardless of their origin.
Managing Treatment and Side Effects
Patients receiving HER2 antibody-drug conjugates are typically administered intravenously. The duration and frequency of infusions can vary depending on the specific drug and the patient’s treatment plan. Healthcare providers closely monitor patients throughout the treatment course to assess effectiveness and manage any potential side effects.
Common side effects associated with HER2 ADCs can include fatigue, nausea, vomiting, and hair loss. Some specific toxicities are related to the drug’s payload or its interaction with HER2 expression in healthy tissues. For example, trastuzumab emtansine (T-DM1) may cause thrombocytopenia (low platelet count) and elevated liver enzymes, while trastuzumab deruxtecan (T-DXd) has been associated with gastrointestinal issues, alopecia, and interstitial lung disease.
Careful monitoring of blood counts, liver function, and respiratory symptoms is standard practice to detect and manage these side effects early. Patient-provider communication is highly important, allowing for prompt reporting of any new or worsening symptoms. Supportive care measures, such as anti-nausea medication or dose adjustments, are often implemented to help patients tolerate treatment and maintain quality of life.