Antibody Drug Conjugates

Author: Dr. Arya Mariam Roy from Roswell Park Comprehensive Cancer Center

 

What are antibody drug conjugates (ADCs)?

Antibody drug conjugates (ADCs) are newer targeted medicines that are specifically designed to deliver chemotherapy agents effectively to a cancer cell without damaging healthy cells. An ADC is composed of a monoclonal antibody (laboratory-produced molecules engineered to serve as substitute antibodies), which is attached to a chemotherapy drug through a chemical connection (linker). They are widely used in several cancers, such as breast cancer, bladder cancer, blood cancer, and lung cancer. Currently, 14 ADCs have been approved worldwide, and several others are being tested in clinical trials.

 

What is the mechanism of action of antibody drug conjugates?

The chemotherapy (called payload) is attached to the monoclonal antibody through a stable connection (called as linker). The ADC is highly targeted and is designed to bind to specific proteins (target antigen) on the surface of cancer cells and then is internalized into the cell. The linkers are highly stable and prevent the splitting of the chemotherapy drug before entering the cancer cell. Once the ADC is inside the cancer cell, the linkage is cleaved, and the chemotherapy is released, which then causes the destruction of the cancer cells (Figure). Some ADCs have a “bystander effect,” in which the payload crosses the cell membrane of the cancer cell and kills the neighboring cancer cells without target antigen expression. The main consideration while designing an ADC is the careful selection of the target antigen; it should be expressed predominantly or exclusively in tumor cells rather than in normal tissues, which prevents its off-target toxicities. For example, the expression of HER2 is very high in several tumors such as breast cancer than in normal cells, which lead to the development of the ADC ado-trastuzumab emtansine and fam-trastuzumab deruxtecan which are widely used in breast cancer treatment now.

 

What are the side effects of antibody-drug conjugates?

Even though ADCs are intended to attach to specific target antigens, most of the chemotherapy they carry ends up being broken down in healthy cells, causing undesired side effects. In some cases, the target antigen can also be present in normal tissues, not just in cancer cells. When this happens, the ADCs bind to these antigens in parts of the body other than the cancer cells, resulting in side effects.

One of the important side effects of ADCs is lung toxicity, particularly in the form of drug-induced inflammation or fibrosis of the lungs, known as interstitial lung disease (ILD). This can happen due to target antigen-dependent uptake of ADC by the lung cells or target-antigen independent update of the antibody drug conjugate by the healthy lung cells or bystander killing effects by the chemotherapy released from cancer cells or circulating free chemotherapy resulting from the early splitting from the linker. The most common symptoms of ILD are tiredness, shortness of breath, cough, chest pain, and fever. Early diagnosis through physical exam, imaging of chest, and prompt treatment using steroid and oxygen supplementation are necessary to prevent death from ILD.

Other reported side effects of ADCs include a decrease in blood cell counts, neuropathy, liver failure, and gastrointestinal issues such as diarrhea and vomiting.