Antibody-drug conjugates (ADCs) are revolutionising the treatment of cancer by combining the specificity of targeted therapy with the potency of cytotoxic chemotherapy, said Dr David Lee, a consultant clinical oncologist.
Speaking at the recent ASCOMOS 2026 meeting in Kuala Lumpur, Lee said ADCs consist of three main components: a monoclonal antibody, a linker and a cytotoxic payload (warhead). The antibody selectively recognises and binds to tumour-associated antigens expressed on cancer cells, and the linker connects the antibody to a highly potent chemotherapeutic agent. Following antigen binding, the ADC is internalised into the tumour cell, where the payload is released intracellularly to induce cell death via mechanisms such as DNA damage or disruption of microtubules and topoisomerase activity.
Additionally, the linker plays a far more important role than is usually believed. The design of the linker not only affects the conjugation of the antibody to the payload but also the stability, efficacy and safety of an ADC. Stable linkers reduce premature release of the drug into the circulation, decreasing systemic toxicity, whereas less stable linkers allow earlier payload release, but can increase off-target effects.
Beware the bystanders
A key feature of many ADCs is the bystander effect. Once released into the tumour microenvironment, some payloads can diffuse across cell membranes and into adjacent cancer cells that have little or no expression of the target antigen. This increases tumour cell killing activity and may improve efficacy in heterogeneous tumours with variable antigen expression among cancer cells.
Recently, ADCs have been of great interest in solid tumours but Lee noted that the technology was first used in haematological malignancies before moving into breast cancer treatment with the introduction of trastuzumab emtansine (T-DM1). Since then, the number of approved ADCs has increased substantially across many tumour types, including lung cancer.
The choice of target antigen remains fundamental to ADC therapy. Human epidermal growth factor receptor 2 (HER2) is still one of the best-characterised targets with separate indications for HER2 over-expression and HER2 mutations. Over-expression of epidermal growth factor receptor (EGFR) and c-MET are other potential targets that reflect the ongoing attempts to broaden the therapeutic spectrum of ADCs. As more targets enter clinical development, biomarker testing will remain central to identifying patients most likely to benefit from treatment.
Although ADCs are designed for targeted distribution, they should not be considered devoid of toxicity. Lee underscored that these agents continue to administer chemotherapy, and their adverse event patterns are indicative of both the properties of the payload and the biology of the antibody target. Toxicities can occur via on-target effects, impacting normal tissues that express the target antigen, or by off-target processes associated with premature payload release or systemic exposure.
Resistance continues to be a significant problem as these cancers may acquire resistance at several phases of the ADC route, encompassing antigen expression, internalisation, intracellular trafficking, lysosomal degradation, and payload efficacy. Given the significant variation in the design of individual ADCs, resistance mechanisms are unlikely to be uniform across the class.
Looking ahead, Lee highlighted several areas of particular interest, including the development of novel antibody formats, such as bispecific antibodies; optimisation of linker chemistry; improved penetration of the blood-brain barrier; and combination strategies with other anticancer therapies. Further advances in biomarker selection and quantification are also expected to further refine patient selection and maximise treatment benefit.
As the number of available ADCs continues to grow, understanding how each of its component affects efficacy and safety will become increasingly important. Continued optimisation of antibody design, linker technology and payload selection is expected to expand the role of ADCs beyond current indications while improving treatment precision and minimising toxicity.