What are Antibody Drug Conjugates?

Antibody Drug Conjugates (ADCs) are medications that can target and deliver medicines to cancer cells. Unlike conventional cancer treatments, such as chemotherapy and radiation, ADCs have the capability to target cancer cells without harming surrounding healthy cells. ADCs are composed of three structural components: the monoclonal antibody, the linker connecting the antibody and the cytotoxic drug, and the cytotoxic, cancer-killing drug.

How do ADCs Work Against Cancer?

ADCs deliver the cytotoxic drugs directly to cancer cells while minimizing the potential damages to surrounding healthy cells. As a result, ADC treatments have the potential to reduce the side effects associated with chemotherapy and other conventional cancer treatments. ADCs work through using monoclonal antibodies, which are proteins that can identify and attach to specific target proteins or receptors on the surface of cancerous cells. The antibody then links to the cytotoxic drug and forms an ADC. ADCs deliver the chemotherapy agents to cancerous cells via the linker, which binds to specific targets on cancer cells. After the linker binds to the target, the ADC releases a cancer-killing drug into cancerous cells.

ADCs are highly advantageous in that they can deliver chemotherapy drugs directly to cancerous cells, effectively minimizing the damages to healthy cells. Because the cancerous cells are directly targeted, there is an increased chance of success in treating the cancer. Additionally, because healthy cells are spared, there is a high chance of lessened side effects from treatment.

What are the types?

There are several types of Antibody-Drug Conjugates, with the most commonly used being:

  • Cleavable Linker ADCs, which use a linker that can be “cleaved”, or severed, by the enzymes within the targeted cells to release the cytotoxic drug. As the drug is released, it kills the cancerous cell.
  • Non-Cleavable Linker ADCs, which use a linker that is internalized into the cancerous cell rather than being cleaved. Once the ADC is internalized, the cytotoxic drug is released into the cancerous cell.
  • Site-Specific Conjugation ADCs, which use linkers that attach to specific sites on the monoclonal antibody. As these linkers attach to specific sites on the monoclonal antibody, they create a more homogenous and effective ADC with better potential to move these drugs throughout the body.
  • Dual-Action ADCs, which combine the cytotoxic drugs with a secondary agent to enhance anti-tumor activity. Common secondary agents include immune checkpoint inhibitors.
  • Bispecific ADCs, which target different antigens on the surface of the cancer cell. This targeting results in higher levels of specificity and potency.
  • Nanoparticle ADCs, which use nanoparticles to deliver cytotoxic drugs to cancerous cells. This direct delivery helps increase the drugs’ stability, as well as strengthening the potential of delivery of the drug.

What Types of Cancer are Treated with Antibody Drug-Conjugates?

There are currently ongoing clinical trials evaluating the types of cancers that can be treated with ADCs. ADCs have been approved by the FDA for treating several types of cancer, including the following:

  • Breast Cancer, specifically HER2-positive and triple-negative
  • Hodgkin Lymphoma and certain types of Non-Hodgkin Lymphoma
  • Urothelial Cancer, specifically advanced or metastatic
  • Lung Cancer, specifically small cell
  • Colorectal Cancer
  • Leukemia, specifically relapsed or refractory acute lymphoblastic leukemia

Drawbacks of Antibody-Drug Conjugates

ADCs offer several advantages compared to conventional cancer treatments, such as chemotherapy, including the targeted delivery of cytotoxic drugs and minimized damages to healthy cells. However, ADCs have potential drawbacks, including:

  • Limited Effectiveness - ADCs have shown to be less effective in treating certain types of cancers, notably solid tumors, due to their inability to penetrate into the tumor’s microenvironment and the unique composition and genetic makeup of each tumor.
  • Potential for Resistance - The body can develop a resistance to ADCs over time due to a variety of factors, including decreased expressions of the target antigen, increased flow of the drug into the body, and mutations in the target’s antigens.
  • Complexity of Manufacturing ADCs - Specialized manufacturing processes are required to create ADCs, which makes them both time-consuming and expensive to create.
  • Toxicity - While ADCs provide a targeted release of cytotoxic drugs, there is still a chance for off-target effects and damages to healthy cells and tissue.
  • Immunogenicity: ADCs can trigger immune responses in some patients, which could lead to the development of antibodies that would reduce the effectiveness of ADC treatment while increasing the chance of negative reactions to the drugs.