Malignant tumors have become the second largest health threat worldwide. However, most chemotherapy drugs have a low therapeutic index and commonly cause serious organ damage unrelated to the treatment purpose. Although targeted drugs can overcome therapeutic bottlenecks, they often act slowly, such as the therapeutic applications of monoclonal antibodies, like Trastuzumab, Rituximab, and Cetuximab, etc.
To enhance treatment effectiveness and reduce the side effects of chemotherapy on non-target sites, a new concept has been proposed: antibody drug conjugates (ADCs). These are monoclonal antibodies chemically linked to cytotoxic drugs through complex linkers, allowing precise drug release at the tumor site, thereby achieving accurate targeting, ensuring effectiveness, and optimizing treatment methods.
Antibody drug conjugates generally consist of three parts: a highly specific and high-affinity monoclonal antibody, a highly stable linker, and a potent small molecule cytotoxic drug. Through the targeting role of the monoclonal antibody, ADCs can accurately deliver cytotoxic drugs to tumor cells that express specific antigens, achieving precise treatment.
Target Antigen Selection
The target antigens expressed on cancer cells are the targets recognized by ADCs. To reduce off-target toxicity, the target antigen should primarily be expressed independently or mostly in tumor cells but rarely or lowly expressed in normal tissues. Ideally, the antigen should be a cell surface (or extracellular) antigen for easy recognition by ADCs. Secondly, the target antigen should be non-secretory because secreted antigens in circulation could lead to extracellular binding, reducing tumor targeting and drug safety. Additionally, after binding to the corresponding antibody, the target antigen should be internalized, allowing the ADC-antigen complex to enter the cancer cells. Subsequently, through proper intracellular transport pathways, the cytotoxic drug is released.
Antibody Component
The tumor-targeting antibody is crucial for the specific binding between the target antigen and the ADC. In addition to high binding affinity to the target antigen, the ideal antibody component should also promote effective internalization, exhibit low immunogenicity, and maintain a long plasma half-life.
Currently, ADCs frequently use fully humanized antibodies with significantly reduced immunogenicity. These antibodies are mostly immunoglobulin G (IgG) antibodies, including four subtypes: IgG1, IgG2, IgG3, and IgG4.
Linker Component
The linker in ADCs connects the antibody to the cytotoxic drug. It is a critical factor affecting the stability of the ADC and the release of its payload, thus significantly impacting the final efficacy of ADCs. The ideal linker should not induce ADC aggregation, should prevent premature payload release, and should facilitate the release of the active drug at the target site.
Cytotoxic Drug
The cytotoxic payload exerts its cell-killing effect once the ADC is internalized into cancer cells. Currently, the cytotoxic payloads used in ADCs mainly include potent microtubule inhibitors, DNA-damaging agents, and immune modulators.
Updated: Apr 15, 2025
