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Key Components of ADC

Antibody-drug conjugates (ADCs) are an emerging and highly potent drug modality that is a good combination of chemotherapy and immunotherapy. ADC consists of a monoclonal antibody with high specificity, a powerful cytotoxic agent as payload, and a linker. Each of the components plays a key role in the efficacy of ADC. The antibody must show specific and selective affinity for antigens present on the target cell surface. The payload needs to be internalized into the target cell and subsequently bound to the designated target to initiate cell death. During the process of antibody and payload binding and their internalization within the target cell, the linker must ensure stable binding between the antibody and payload and effectively dissociate the payload at the appropriate moment.

Amerigo Scientific offers various cytotoxic payloads, linkers, and drug-linker conjugates for the preparation of ADCs.

Antigen Selection

Antigen selection is a key step in the development of ADC. The target antigen specifically recognized by the antibody component needs to be highly expressed in the abnormal cells (e.g. tumor cells), but not expressed or poorly expressed in normal cells. The target antigen should be displayed on the cell surface so that circulated antibodies can recognize it. In addition, the target antigen should be internalized upon binding to the ADC, which would facilitate ADC transport into the cell and thus enhance the efficacy of the cytotoxic payload. Bystander killing occurs when the cytotoxic agent from an ADC is released from the target cell after internalization and degradation of the ADC or when the agent is released in the extracellular space. The extent to which ADC mediates bystander killing depends largely on factors such as the degree of ADC internalization upon binding to the target antigen, the presence of uncleavable or cleavable linkers, and the hydrophobicity of the cytotoxic payload.

ADC Development

An ideal ADC remains stable in the blood circulation, accurately reaches the therapeutic target, and eventually releases a cytotoxic payload near the target. Ideal antibodies for ADC construction should have target specificity, target-binding affinity, good retention, low immunogenicity, low cross-reactivity, and appropriate linkage-binding properties. Optimization of the binding affinity of the antibody is a key step in maximizing ADC efficacy. However, excessively strong antigen binding may result in retention of ADC on the target cell surface, thereby limiting the extent of tissue penetration. Therefore, the antibody moiety of an ADC must be carefully selected, considering various parameters to ensure optimal performance of the ADC. ADC linker is one of the key factors related to the stability and payload release of the ADC and is therefore very important for the ultimate therapeutic index of the ADC. An ideal linker should not induce ADC aggregation and is expected to limit the premature release of the payload in the plasma and facilitate the release of the active drug at the desired target site. The cytotoxic payload exerts cytotoxicity after the ADC is internalized into the target cell. Compounds used as ADC payloads need to be highly potent and keep stable under physiological conditions. In addition, the method by which the drug-linker conjugate is bound to the antibody is also important for the successful construction of the ADC.

Each element affects the efficacy and safety of an ADC, so the development of an ADC needs to consider the choice of target antigens, antibodies, cytotoxic payloads, linkers, and conjugating methods. Amerigo Scientific provides a wide range of reagents and kits for the research and development of ADCs.