Tumours, in the future there will be many 'magic bullets': here are the ADC drugs

Since 2000, when the first ADC was put on the market (it was gemtuzumab ozogamicin), the number of drugs available in this category has grown rapidly: in 2025 there were 19 ADCs approved worldwide, (a dozen in the last five years alone) most of which (as many as 13) are for solid tumours. And alongside those already approved, there are at least 50 more in advanced stages of clinical development. Thanks to new molecular engineering technologies, ADCs today are much more stable and precise than in the past. But although the list of indications grows longer every year, these drugs cannot currently be used to treat so many forms of cancer.

ADCs do not merely 'transport' a drug to a target. The latest generation ADCs are examples of 'smart' therapies. Their antibodies recognise specific targets on tumour cells and lock onto them, but they are not limited to simply delivering a drug to the heart of the tumour.

In fact, some ADCs are also able to activate the immune system. Through particular interactions with immune defence cells and proteins, they can stimulate mechanisms that help the body attack the tumour directly. And there are several new-generation ADCs designed to boost the anti-tumour immune response. Others, however, have been modified to avoid unwanted interactions with healthy tissues, such as liver and bone marrow, thus reducing the risk of toxicity.

A particularly interesting aspect is the so-called 'bystander effect'. When the drug is released on the tumour, it can also spread to cancer cells that may not exhibit the target recognised by the antibody. This makes it possible to target very heterogeneous tumours, where not all cells are identical.

Scientists are also investigating even more sophisticated systems to exploit typical features of the tumour microenvironment - for example, the high presence of enzymes called proteases - to deliver the drug directly to the tumour site. In this way, ADCs could also work against tumours that express few molecular targets.

Finally, some of the substances carried by ADCs appear to cause an 'immunogenic' death of cancer cells, i.e. a death capable of 'waking up' the immune system against cancer. And this opens the way for very promising combinations with immunotherapy, such as immune checkpoint inhibitors.

ADCs are often referred to as 'three drugs in one' because they combine three elements: an antibody that recognises the tumour, a toxic drug that kills cancer cells, and a chemical link that holds them together.

Since developing new antibodies is complex and risky, many companies have chosen to modify only part of the ADC, for example by changing the drug carried but keeping the same antibody. One example is the anti-HER2 ADCs, which are mainly used in breast cancer: today there are already five approved.

Some modifications have led to successful results. This was the case with trastuzumab deruxtecan (T-DXd), which showed superior efficacy compared to earlier drugs and promising results even in tumours with low HER2 levels. In other cases, however, changing the toxic 'load' was not enough to achieve effective or safe drugs.

Clinical experience has also shown that, even using already well-known antibodies, each new ADC must be carefully evaluated for possible side effects, such as the risk of inflammatory lung disease, observed with some treatments.

Research is now focusing on next-generation ADCs, containing antibodies capable of recognising several targets at the same time or equipped with more selective delivery systems, or containing drugs that are also active in tumours with few markers, or finally designed to be administered in combination with immunotherapy. The aim is to extend the efficacy of these therapies, even in tumours hitherto 'off limits', while keeping toxicity under control.

This category of drugs is changing the way many advanced cancers are treated, but could soon be used in the earliest stages of cancer.

The challenge in the coming years will be to understand which patients can benefit most from it and how best to manage side effects. But one thing already seems clear: the 'magic bullet' imagined over a century ago is no longer just a theoretical dream, but an increasingly concrete reality in modern oncology.