Antibody–drug conjugates (ADCs)
Target selection
ADCs are sometimes referred to as ‘biological missiles’, where the (typically cytotoxic) drug is the ‘warhead’ or ‘payload’ and the antibody provides the ‘guidance system’ that directs the drug to the target cell. Whilst innovation is bringing forward ADC applications outside of oncology, the typical target of currently approved ADCs is an antigen that is strongly and selectively expressed on the surface of cancer cells. This allows the guidance system to direct the drug to the cancer with minimal off-target damage to healthy cells.
The internalisation behaviour of the antigen is also important: most ADCs need to be internalised and delivered to the lysosome for their ‘payload’ to be effective. This mode of action means that targets
which are slowly internalised or recycled to the plasma membrane without delivery to the lysosome have so far been generally avoided.
A challenge for accurate targeting of the ‘biological missile’ is that most tumour antigens are not truly tumour specific. There is usually at least some expression in healthy tissues, creating a risk of off-target effects. This challenge is driving innovation in a number of areas, including bispecific ADCs (bsADCs), since a combination of two targets may label a tumour cell more specifically than a single antigen on its own. The use of dual target or dual epitope binding also offers other possibilities to optimise function. For example, binding two antigens can modulate internalisation by ‘piggybacking’ on the rapid internalisation of one of the antigens or by promoting the formation of higher-order structures.
Payload
Perhaps the most fundamental component of an ADC after the antibody is the drug, most often referred to as a payload. The payloads of currently approved ADCs (as of 2024) mainly fall into two classes – DNA damaging agents and microtubule inhibitors. The DNA damaging agents currently employed are of three types, calicheamicins (N-acetyl gamma calicheamicin), pyrrolobenzodiazepine dimers (tesirine) and topoisomerase inhibitors (SN-38 and deruxtecan), each of which acts in a different manner. The microtubule inhibitors fall into two classes, auristatins (MMAE) and maytansinoids (DM1 and DM4). MMAE is the most common payload, featuring in five approved ADCs.
There are many ADCs in development with a broader range of payloads. Some of these fall into the classes discussed above with additional auristatins,
maytansinoids, tubulysins, duocarmycins, diazepine compounds and topoisomerase inhibitors having been disclosed. However, new classes of payloads are also being researched, including immunomodulators (such as STING agonists and TLR7/8/9 agonists), RNA polymerase II inhibitors and degraders (such as PROTACs, GSPT1 degraders, BRD4 degraders and, RIPK2 degraders). Beyond these, there is a huge range of further avenues such as steroids, siRNA and NMT inhibitors, to name but a few.
Not satisfied with ADCs delivering a single payload in a targeted manner, there is growing interest in ADCs capable of delivering two (or more!) payloads. For example, the Scripps Research Institute developed a PNU-159682 and MMAF dual-payload ADC, where the two payloads are separately conjugated to the HER2 targeting antibody.
"One strategy to pursue patent protection for the payloads is to treat them in the same way as standalone small molecule agents, with care taken to ensure that there is coverage of both the compound that is an intermediate in the ADC synthesis, as well as the released drug."
© 2025 Mewburn Ellis
