Antibody-Drug Conjugates (ADCs) are a novel class of targeted cancer therapies that combine the high specificity of monoclonal antibodies with the potent cell-killing ability of cytotoxic drugs. By precisely delivering chemotherapy agents directly to tumor cells, ADCs offer a powerful dual advantage—targeted binding and effective tumor cell eradication. This innovative modality has emerged as one of the fastest-growing therapeutic strategies in oncology.
Key Components of ADC Drugs
Monoclonal Antibody (Antibody) – The Navigation System
The monoclonal antibody is engineered to specifically recognize and bind to antigens expressed on the surface of tumor cells, functioning like a “key fitting a lock.” This precise targeting ensures the drug homes in on cancer cells while sparing healthy tissue.
Linker –The Stability Chain
The linker connects the antibody to the cytotoxic payload via a covalent bond. A well-designed linker ensures stability in the bloodstream, preventing premature drug release and guaranteeing the toxic payload reaches its tumor target safely.
Cytotoxic Payload – The Warhead
These are highly potent chemotherapeutic agents that are far more effective than conventional chemotherapy drugs. Once released inside the tumor cell, they destroy the cell by disrupting vital intracellular processes.
Primary Mechanism of Action
After intravenous administration, the ADC circulates through the bloodstream and binds to specific antigens on the surface of tumor cells. This antigen-ADC complex is internalized via receptor-mediated endocytosis. Once inside the cell, some complexes are routed to lysosomes, where the linker is cleaved and the active cytotoxic drug is released. This drug then interferes with critical cellular mechanisms, ultimately leading to apoptosis (programmed cell death).
In some cases, part of the ADC-antigen complex is recycled back into circulation via the FcRn receptor pathway, serving as a protective buffer against off-target toxicity in normal cells.
The Bystander Effect
The bystander effect allows ADCs to eliminate neighboring cancer cells that may not express the target antigen (Ag-), including heterogeneous tumor cells and metastatic lesions. This phenomenon significantly enhances therapeutic efficacy but depends on several biochemical factors:
Linker Stability
ADCs with unstable linkers may release the toxic payload before internalization, allowing diffusion into surrounding cells. Cleavable linkers (e.g., pH-sensitive hydrazone bonds, disulfide bonds, enzyme-sensitive dipeptides) are more prone to inducing a bystander effect. In contrast, non-cleavable linkers (e.g., stable thioether bonds) require lysosomal degradation within tumor cells.
Cytotoxic Payload Properties
The chemical polarity of the payload plays a crucial role. Low-polarity payloads can permeate cell membranes and affect neighboring cells, while highly polar compounds remain trapped inside the target cell. A unique example is T-DM1, which, despite having a relatively small polar payload, does not exert a bystander effect due to incomplete cleavage and the presence of a positively charged lysine residue, which limits membrane permeability.
Tumor Cell Lysis
When tumor cells are ultimately destroyed, they may release intracellular toxins into the tumor microenvironment, contributing to the bystander effect.
Anti-Tumor Immunity and Cytokine Activation Pathways
The antibody component of ADCs also plays a role in immune activation:
- Complement-Dependent Cytotoxicity (CDC)
- Antibody-Dependent Cellular Cytotoxicity (ADCC)
- Antibody-Dependent Cellular Phagocytosis (ADCP)
Through these pathways, the antibody fragment (Fab) recognizes tumor-specific or virus-infected antigens, while the Fc region engages immune effector cells such as NK cells and macrophages via Fc receptors. This interaction facilitates direct immune-mediated tumor killing.
Some ADC antibodies retain biological activity and can block signaling pathways essential for tumor growth, offering additional anti-tumor effects independent of the cytotoxic payload.