ADC Detailed Explanation Series: Target Selection in Cancer Therapy
The article provides a comprehensive overview of antibody-drug conjugates (ADCs) and their targets in cancer therapy. It explores the rationale behind ADC development, emphasizing the importance of target selection, linker stability, and payload potency. The chapter discusses various targets used in ADC therapy, such as HER2, CD30, and CD33, highlighting their role in tumor cell targeting. It also covers the mechanism of action of ADCs, including target binding, internalization, and payload release.
What is ADC in pharmaceutical sector?
ADC (Antibody–Drug Conjugates), the full name of "antibody-drug conjugates", is a type of targeted drug composed of antibodies, linkers, and cytotoxic drugs. It uses monoclonal antibodies as carriers to efficiently transport cytotoxic drugs in a targeted manner. into target tumor cells, combining the powerful killing effect of traditional chemotherapy and the tumor targeting of antibody drugs. The ideal ADC drug remains stable in the blood circulation, accurately reaches the therapeutic target, and ultimately releases the cytotoxic payload near the target (such as cancer cells). For ADC drugs to achieve ideal efficacy and safety, five core elements need to be comprehensively considered when constructing ADC: target, antibody, linker, toxin, and conjugation method.
Figure 1. Structure and properties of ADC drugs
The mechanism of action of ADCs starts with their binding to target cells, guided by the presence of specific antigens on tumor cells. Once bound, ADCs are internalized through endocytosis and transported within the tumor cell. Ultimately, the ADC undergoes degradation, releasing the cytotoxic payload to induce cell death. Selecting the appropriate target antigen is critical for ADC efficacy, as it determines the specificity of the therapy for tumor cells. By targeting antigens expressed predominantly on cancer cells, ADCs can deliver cytotoxic drugs specifically to tumor cells, maximizing therapeutic benefit while minimizing off-target effects.Target properties: an ideal target should have the following characteristics:
(1) Strong tissue specificity
To minimize off-target toxicity, an ideal ADC target should be highly specific to tumor tissues, with minimal or no expression in normal cells. For instance, HER2 is overexpressed about 100 times more in certain tumors than in normal cells. This specificity helps ensure that the ADC predominantly targets cancer cells, enhancing its therapeutic efficacy while reducing the risk of harming healthy tissues. Such precise targeting is crucial for improving treatment outcomes and minimizing side effects associated with traditional chemotherapy, highlighting the importance of selecting antigens that exhibit strong tissue specificity for ADC development.(2) High antigen stability
To maintain effective tumor targeting and avoid safety concerns, the ideal ADC target antigen should be stable and located on the cell surface or extracellularly, rather than intracellularly. Intracellular antigens are less accessible to ADCs and may lead to reduced efficacy. Additionally, the target antigen should not be secreted to prevent detection by the circulatory system, which could result in off-target effects. A stable, surface or extracellular target antigen enhances the specificity of ADCs for cancer cells, improving their ability to deliver cytotoxic payloads precisely to tumor cells while minimizing systemic toxicity.(3) Efficient internalization of antigen
Efficient internalization of the target antigen is crucial for ADC efficacy. Upon binding to the corresponding antibody, the ideal target antigen should undergo internalization, allowing the ADC to enter cancer cells. This internalization process enables the ADC to navigate through appropriate intracellular transport pathways, ultimately leading to the release of cytotoxic payloads within the cancer cell. This mechanism enhances the specificity of the therapy, ensuring that the cytotoxic drugs are delivered precisely to the target cells while minimizing exposure to healthy tissues. An antigen that facilitates efficient internalization is therefore essential for maximizing the therapeutic potential of ADCs in cancer treatment. The target antigens of currently approved ADC drugs are typically proteins that are specifically overexpressed by cancer cells. These targets include HER2, Trop2, Nectin4, and EGFR in solid tumors, as well as CD19, CD22, CD33, CD30, BCMA, and CD79b in hematological malignancies. The selection of these antigens has been driven by advancements in oncology and immunology research. Over time, there has been a shift from targeting traditional tumor cell antigens to including targets within the tumor microenvironment, such as those found in the extracellular matrix and vasculature. This expansion in target selection has broadened the potential applications of ADCs in cancer therapy.
Figure 2. ADC drug target selection (tumor cells and tumor microenvironment)
ADC targets approved for marketing
Since the FDA approved the first ADC drug, Mylotarg® (gemtuzumab ozogamicin), in 2000, a total of 14 ADC drugs have been approved worldwide for treating hematological malignancies and solid tumors as of 2024. These 14 drugs target 12 specific antigens: HER2, CD22, BCMA, CD33, CD30, CD79b, Nectin-4, EGFR, CD19, Tissue Factor (TF), FRα, and Trop2.| Number | Drug name | Company | Target | Cytotoxic drugs | Connector | DAR | Approval time |
| 1 | Mylotarg | Pfizer | CD33 | calicheamicin | Acid hydrolysis of hydrazone bonds and disulfide bonds | 2-3 | 2000.05.17 |
| 2 | Adcetris | Seattle | CD30 | MMAE | MC-VC-PABC | 4 | 2011.08.19 |
| 3 | Kadcyla | Roche | HER2 | DM1 | MCC | 3.5 | 2013.02.22 |
| 4 | Besponsa | Pfizer | CD22 | calicheamicin | Acid hydrolysis of hydrazone bonds and disulfide bonds | 5-6 | 2017.06.28 |
| 5 | Polivy | Roche | CD79b | MMAE | MC-VC-PABC | 3.5 | 2019.06.10 |
| 6 | Padcev | Seattle | Nectin-4 | MMAE | MC-VC-PABC | 3.8 | 2019.12.18 |
| 7 | Enhertu | Daiichi Sankyo | HER2 | Dxd | MC-GGFG | 7-8 | 2019.12.20 |
| 8 | Trodelvy | Immunomdecls | Trop-2 | SN38 | Acid cleaves carbonate bonds | 7.6 | 2020.04.22 |
| 9 | Blenrep | GSK | BCMA | MMAE | Uncut MC | 4 | 2020.08.05 |
| 10 | Akalux | Rakuten Medical | EGFR | IRDye700DX | N/A | 1.3-3.8 | 2020.09.25 |
| 11 | Zynlonta | ADC Therapeutics | CD19 | PBD | PEG8-VA-PABC | 2.3 | 2021.04.23 |
| 12 | Vidicil | Rongchang Biology | HER2 | MMAE | MC-VC-PABC | 4 | 2021.06.08 |
| 13 | Tlvdak | Genmab/Sesgen | TF | MMAE | MC-VC-PABC | 4 | 2021.09.20 |
| 14 | Elahere | ImmunoGen | ERα | DM4 | SPDB | 3 | 2022.11.14 |
Table 1. Marketed ADC drug targets
ADC target research and development status
Statistics indicate that over 800 ADC drugs are currently in various stages of development globally. These drugs target a range of popular antigens, including HER2, Trop2, EGFR, c-Met, B7-H3, HER3, Nectin-4, CLDN18.2, and PDL1. These targets are considered mature and have shown promise in developing ADC therapies. The diversity of targets reflects ongoing efforts to expand the utility and effectiveness of ADCs in treating various cancers. This broad development pipeline underscores the growing interest and investment in ADC research and development worldwide.
Figure 3. Global distribution of ADC targets under development (top 20) (as of 2022)
Common targets of ADC drugs in the field of lung cancer
The exploration of ADC drugs in the field of lung cancer mainly targets HER2, HER3, Trop2, MET, CEACAM5, B7-H3 and other targets (Figure 4), and has shown great application potential.
Figure 4. Overview of lung cancer ADC drug targets
