ADC (Antibody-Drug Conjugates) are targeted drugs composed of antibodies, linkers, and cytotoxic drugs. They use monoclonal antibodies as carriers to efficiently deliver cytotoxic drugs to target tumor cells in a targeted manner, combining the powerful killing effect of traditional chemotherapy with the tumor-targeting specificity of antibody drugs.
An ideal ADC drug remains stable in the bloodstream, precisely reaches the therapeutic target, and ultimately releases the cytotoxic payload near the target (e.g., cancer cells). To achieve optimal efficacy and safety of ADC drugs, five core elements need to be considered in their construction: target, antibody, linker, toxin, and conjugation method.
![Figure 1. Structure and Characteristics of ADC Drugs [1]](https://e1752fbe.rocketcdn.me/wp-content/uploads/Figure-1.-Structure-and-Characteristics-of-ADC-Drugs-1.png "Figure 1. Structure and Characteristics of ADC Drugs [1]")
The mechanism of action of ADCs begins with binding to target cells. The target antigen expressed on tumor cells guides ADC drugs to recognize tumor cells. After binding to the antigen, ADC drugs must also be internalized and transported and degraded within tumor cells. Therefore, selecting an appropriate target is one of the primary considerations for ADCs.
Characteristics of Targets
An ideal target should have the following characteristics:
- High tissue specificity: To reduce off-target toxicity, the target antigen should be expressed only or mainly in tumor cells and have low or no expression in normal tissues. For example, the expression of HER2 in certain tumors is about 100 times higher than in normal cells.
- High antigen stability: To avoid reduced tumor targeting and safety issues, the target antigen should be a surface (or extracellular) antigen rather than an intracellular antigen, and it should be non-secretory to avoid recognition by the circulatory system.
- Efficient antigen internalization: The ideal target antigen should be internalized after binding with the corresponding antibody, allowing the ADC drug to enter cancer cells and release the cytotoxic payload through appropriate intracellular transport pathways.
Currently approved ADC drugs target specific proteins overexpressed in cancer cells, including targets in solid tumors such as HER2, Trop2, Nectin4, and EGFR, as well as targets in hematologic malignancies such as CD19, CD22, CD33, CD30, BCMA, and CD79b. Driven by basic research in oncology and immunology, the selection of ADC target antigens has gradually expanded from traditional tumor cell antigens to targets in the tumor microenvironment (e.g., in the stroma and vasculature).
![Figure 2. Selection of ADC Drug Targets (Tumor Cells and Tumor Microenvironment) [1]](https://e1752fbe.rocketcdn.me/wp-content/uploads/Figure-2.-Selection-of-ADC-Drug-Targets-Tumor-Cells-and-Tumor-Microenvironment-1.png "Figure 2. Selection of ADC Drug Targets (Tumor Cells and Tumor Microenvironment) [1]")
Approved ADC Targets
Since the first ADC drug, Mylotarg® (gemtuzumab ozogamicin), was approved by the FDA in 2000, a total of 14 ADC drugs have been approved globally for hematologic malignancies and solid tumors as of 2024. These 14 ADC drugs correspond to 12 targets: HER2, CD22, BCMA, CD33, CD30, CD79b, Nectin-4, EGFR, CD19, Tissue Factor (TF), FRα, and Trop2.
Read more about ADC Drugs Already Marketed Globally: Compilation of Technical Reviews.
Research and Development of ADC Targets
According to statistics, more than 800 ADC drugs are in various stages of development worldwide. Popular ADC targets include HER2, Trop2, EGFR, c-Met, B7-H3, HER3, Nectin-4, CLDN18.2, and PDL1, among other mature targets.
![Figure 3. Global Distribution of ADC Targets in Development (Top 20) [2]](https://e1752fbe.rocketcdn.me/wp-content/uploads/Figure-3.-Global-Distribution-of-ADC-Targets-in-Development-Top-20-2-1024x505.png "Figure 3. Global Distribution of ADC Targets in Development (Top 20) [2]")
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Common Targets of ADC Drugs in Lung Cancer
The exploration of ADC drugs in the field of lung cancer mainly targets HER2, HER3, Trop2, MET, CEACAM5, and B7-H3 (Figure 4), showing great potential for application.
![Figure 4. Overview of ADC Drug Targets in Lung Cancer [3]](https://e1752fbe.rocketcdn.me/wp-content/uploads/Figure-4.-Overview-of-ADC-Drug-Targets-in-Lung-Cancer-3.png "Figure 4. Overview of ADC Drug Targets in Lung Cancer [3]")
HER2 Target
HER2 is a receptor tyrosine kinase (RTK) considered a therapeutic target for non-small cell lung cancer (NSCLC). HER2 is less prone to internalization and degradation compared to other HER family members, exhibiting higher receptor turnover. Therefore, it can remain activated on the cell membrane for a longer time, representing an ideal target for ADC development.
Read more about HER2:
Why Human epidermal growth factor receptor 2 (HER2) is an attractive target for ADC;
HER2, the first ADC drug for HER2-positive gastric cancer, approved in Japan
HER3
Target HER3 is another member of the RTK HER family, commonly expressed in NSCLC (up to 83%). HER3 heterodimerization is a mechanism of resistance to EGFR tyrosine kinase inhibitors (TKIs), playing a role by enhancing HER3-dependent oncogenic signal activation.
Trop2 Target
Trop2 is a transmembrane glycoprotein of the epithelial cell adhesion molecule (EpCAM) family, expressed in most tumors but occasionally in normal tissues.
CEACAM5 Target
Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) are a family of cell surface glycoproteins. CEACAM5 is selectively expressed in several tumor types, including lung cancer.
MET Target
MET is a tyrosine kinase receptor for hepatocyte growth factor. In NSCLC, MET overexpression occurs in about 30%-50% of cases, while MET amplification (1.5%) or MET exon 14 skipping mutations (3%) are major oncogenic drivers.
B7-H3 Target
B7-H3 (also known as CD276) is an important immune checkpoint molecule of the B7 family, with its ligand still unclear, and is highly expressed in cancer cells.
In the field of lung cancer, in addition to the above targets, other targets such as EGFR, AXL, and PVRL4 are also in clinical development.
In summary, the competition in the ADC field is becoming increasingly intense, with significant homogeneity in target selection. Most targets are in the stage of clinical efficacy validation. How to optimize target selection from different dimensions such as technology and indications, and differentiate target advantages, will be the direction of future exploration.
Read more about ADC linker related articles:
What is ADC(Antibody-drug Conjugates)?
What is the difference between ADC linker and PEG linker?
ADC Linker Design and ADC Empowerment
Advances in ADC Linker Research
References:
[1] Fu Z, Zhang Y. Antibody drug conjugate: the “biological missile” for targeted cancer therapy. Signal Transduct Target Ther. 2022;7(1):93
[2] https://www.pharmcube.com/
[3] Passaro A, Jänne PA, Peters S. Antibody-Drug Conjugates in Lung Cancer: Recent Advances and Implementing Strategies. J Clin Oncol. 2023 Jul 20;41(21):3747-3761. doi: 10.1200/JCO.23.00013. Epub 2023 May 24.