HER2 ADCs, or Human Epidermal Growth Factor Receptor 2 Antibody-Drug Conjugates, are a class of drugs designed to deliver potent chemotherapy agents directly to cancer cells. By precisely targeting specific cancer-associated proteins, HER2 ADCs aim to improve treatment efficacy and reduce systemic side effects compared to conventional chemotherapy.
The Components: HER2 and Antibody-Drug Conjugates
HER2 is a protein found on the surface of cells. It is a member of the epidermal growth factor receptor (EGFR) family, which plays a role in regulating normal cell growth and differentiation. In some cancers, the HER2 gene can be amplified, leading to an excessive number of HER2 proteins on the cell surface, known as HER2 overexpression. This drives uncontrolled cell proliferation and tumor growth, characterizing HER2-positive cancers.
Antibody-Drug Conjugates (ADCs) combine the specificity of antibodies with chemotherapy drugs. An ADC consists of three main parts: a monoclonal antibody, a potent cytotoxic drug (the payload), and a linker that chemically connects the antibody to the drug. The monoclonal antibody acts as a targeting mechanism, designed to recognize and bind to specific antigens, such as HER2, found on the surface of cancer cells.
The payload is a potent chemotherapy agent responsible for killing cancer cells once released. The linker is a crucial component that ensures the stability of the ADC in the bloodstream, preventing premature release of the toxic payload before it reaches the target cancer cell. Different types of linkers exist, with some being cleavable by enzymes found within cancer cells, while others are non-cleavable and rely on the degradation of the antibody within the cell to release the payload.
How HER2 ADCs Target Cancer
Once administered, the ADC’s monoclonal antibody specifically recognizes and binds to the HER2 proteins overexpressed on cancer cells. This binding initiates receptor-mediated endocytosis, where the entire ADC-HER2 complex is internalized into the cancer cell.
Upon internalization, the ADC is transported to compartments within the cell, such as endosomes and lysosomes. Inside these cellular structures, the linker connecting the antibody and the chemotherapy drug is cleaved by specific enzymes. For example, trastuzumab deruxtecan (Enhertu) uses a cleavable tetrapeptide-based linker, allowing the release of deruxtecan (DXd), a topoisomerase I inhibitor. Ado-trastuzumab emtansine (Kadcyla) utilizes a non-cleavable thioether linker, with the payload, DM1, released upon lysosomal degradation of the antibody.
Once released, the chemotherapy payload interferes with essential cellular processes, leading to cancer cell death. For instance, deruxtecan causes DNA damage by inhibiting topoisomerase I, while DM1 inhibits microtubule polymerization, disrupting cell division. A key advantage of this targeted delivery is the “bystander effect,” where the released payload can also affect neighboring cancer cells, even those with lower HER2 expression, further enhancing anti-tumor activity.
Cancers Treated with HER2 ADCs
HER2-positive breast cancer is a primary indication for these therapies, where HER2 is overexpressed in approximately 15-30% of invasive cases. Ado-trastuzumab emtansine (Kadcyla) was among the first HER2 ADCs approved, initially for metastatic HER2-positive breast cancer that had progressed after prior treatments. Its approval was later expanded for adjuvant treatment in early breast cancer. Trastuzumab deruxtecan (Enhertu) is also approved for HER2-positive breast cancer, including patients who have received two or more prior anti-HER2 regimens.
Beyond breast cancer, HER2 ADCs have received approvals for other malignancies. Trastuzumab deruxtecan, for instance, is approved for HER2-positive gastric or gastroesophageal junction adenocarcinoma, especially in cases that have progressed after a prior trastuzumab-based regimen.
The utility of HER2 ADCs is also expanding to “HER2-low” breast cancer, a subset previously not considered eligible for HER2-targeted therapies. Trastuzumab deruxtecan has demonstrated efficacy in these patients, defined by lower levels of HER2 expression (IHC 1+ or IHC 2+ with negative FISH). Ongoing research is exploring the use of HER2 ADCs in other solid tumors with HER2 overexpression or mutations, such as specific types of non-small cell lung cancer, colorectal cancer, uterine cancer, and ovarian cancer. Determining a patient’s HER2 status through testing, typically via immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), is a prerequisite for considering these therapies.
What to Expect During HER2 ADC Treatment
Patients receive HER2 ADC treatment through intravenous (IV) infusion in a hospital or clinical setting. The specific dosing schedule, such as infusions every three weeks, can vary depending on the particular ADC being administered and the patient’s treatment plan. Healthcare providers closely monitor patients during infusions for any immediate reactions.
While HER2 ADCs are designed to be more targeted than traditional chemotherapy, they can still cause side effects because some healthy cells may also express HER2 or be affected by the potent payload. Common side effects reported across HER2 ADCs include fatigue, nausea, and decreased appetite, with nausea being very prevalent, observed in about 40-70% of patients. Hair thinning or loss can also occur.
More specific toxicities require careful monitoring. Interstitial lung disease (ILD) or pneumonitis, an inflammation of the lungs, has been observed with some HER2 ADCs like trastuzumab deruxtecan, occurring in approximately 20% of patients in some analyses, with a median onset around 5.6 months. Hematological toxicities, such as thrombocytopenia (low platelet count), anemia, and neutropenia (low white blood cell count), are also known side effects. Additionally, some ADCs may carry a risk of cardiac dysfunction, including a reduction in left ventricular ejection fraction, necessitating regular heart function assessments. Healthcare providers, including oncologists and pharmacists, actively monitor patients for these adverse events, providing supportive care and adjusting treatment as needed to manage side effects and ensure patient safety.