The story of ADCs began nearly a century ago – in the mind of an infamous German scientist and Nobel laureate, whose name has become synonymous with two defining treatments in oncology.

At the turn of the 20th century, in a country that no longer exists, Dr Paul Ehrlich occupied his working days studying the therapeutic properties of chemical dyes. As he methodically pipetted droplets of liquid onto different tissue samples, he began to notice an unusual pattern. Not all dyes behaved the same way. Some would stain certain cells, but leave others completely untouched. Others would stain only a specific part of a cell. It was, he theorised, as if they had a built-in roadmap telling them where to go.

Using his foundational knowledge of chemistry, Ehrlich reasoned that, in the same way that dye molecules were known to have side chains related to their colouring properties, living cells must also have these ”side chains” that would break off and hunt down toxins. It was these toxin-hunting antibodies that gave life to Ehrlich’s theory, Zauberkugel, or "magic bullet” for those who don’t speak German.

By the 1970s, scientists had successfully mapped the molecular structure of antibodies. Thanks to advancements in both biology and technology, they could now produce antibodies by injecting a target antigen into an animal and harvesting the diverse array of antigens produced by the animal's immune system. The problem was that the resulting antibody mixtures – known as polyclonal antibodies - lacked specificity and batch-to-batch uniformity, making it difficult to replicate experiments or compare results.

Armed with this breakthrough, scientists began testing some of the first experimental ADCs in the 1980s. Early attempts linked antibodies to highly potent cancer drugs, but the results exposed significant challenges, including unstable linkers, toxic payloads that detached before reaching their targets, and unintended immune reactions. The promise was evident, but just as Dr Ehrlich had found, the technology wasn’t ready to realise it.

After decades of dedicated research building toward the first ADC approval, anticipation was at an all-time high in 2000 when the US Food and Drug Administration green-lit accelerated approval for the first of its kind, gemtuzumab ozogamicin (marketed as Mylotarg by Wyeth) for patients with CD33-positive acute myeloid leukaemia (AML). At long last, Ehrlich's century-old vision of a targeted “cancer killing” therapy had been realised.

Unfortunately, the success story would quickly become a cautionary tale for the industry.

The problems began early. Traditional FDA approvals required randomised, controlled trials showing solid safety and efficacy results against a disease. But, because Mylotarg was the first AML drug to be brought to market in 15 years, it met the criteria for accelerated approval, which required a lower standard of proof before approval – most notably, there was no empirical evidence that the drug improved survival rates.

While Mylotarg's withdrawal appeared to cast doubt on the future of ADCs, the drug had left a legacy that was difficult for researchers to ignore: selective delivery of highly potent cytotoxins to cancer cells was clinically achievable.

And so, undeterred by this minor setback, researchers used the lessons of gemtuzumab ozogamicin to refine every component of ADC design - from the antibodies themselves to the chemistry linking them to their cytotoxic payloads.

A second milestone followed just two years later. In 2013, ado-trastuzumab emtansine (Kadcyla) gained approval for HER2-positive breast cancer. The culmination of decades of research into HER2 biology and the foundation of success laid by trastuzumab, Kadcyla became the first ADC approved for a solid tumour, further demonstrating the promise of ADCs beyond liquid tumours.

By the second half of the 2010s, ADCs had evolved from a promising niche technology into one of the most closely watched areas in oncology.

Among the many advancements in ADC research during these five years, perhaps the most transformative was the emergence of topoisomerase I (TOP1) inhibitor payloads. Unlike earlier, highly toxic payload classes, these potent compounds enabled researchers to achieve safer, more precise release inside cancer cells, giving rise to a new generation of therapies, including trastuzumab deruxtecan (T-DXd), datopotamab deruxtecan, and acituzumab govitecan.

After seven years in exile, it was time for a familiar name to make a long-awaited comeback. In September 2017, gemtuzumab ozogamicin officially returned to the market, having secured re-approval for the treatment of adults with newly diagnosed CD33-positive AML, as well as the treatment of patients aged two years and older with CD33-positive relapsed/refractory AML. Only, this time, the drug came with revised dosing schedules and a better understanding of how to manage its risks.

In 2019, a flurry of new approvals, including enfortumab vedotin (brand name, Padcev) and polatuzumab vedotin (Polivy), expanded the reach of ADCs into new disease settings and validated additional molecular targets.

By the early 2020s, ADCs had become one of the most promising areas in oncology, attracting billions of dollars in partnerships, acquisitions, and research programmes as companies raced to secure a position in what many viewed as the next frontier of precision medicine.

Much of this excitement was driven by the stand-out success of trastuzumab deruxtecan. Building on its initial approval, the therapy continued to redefine the status quo of cancer treatment with new data across multiple settings, fuelling heightened interest in HER2-directed conjugates and the broader application of the platform.

For much of their development, ADCs were evaluated one at a time. But, in 2024, that approach shifted with the publication of the first Dual ADC (DAD) trial, combining enfortumab vedotin and sacituzumab govitecan. In the study, researchers sought to understand whether two ADCs with different targets could be given together, a question that challenged commonly held beliefs that combining ADCs would compromise safety. Results, presented at ESMO 2023, revealed the opposite: a 70% objective response rate in treating heavily pretreated, metastatic urothelial carcinoma.

Having cemented its reputation in the ADC landscape, Enhertu added a number of important notches to its belt in 2025, including positive results in early breast cancer, and then in the 'post-neoadjuvant' setting, as well as approvals in Europe for use in advanced breast cancer cases with lower levels of the HER2 biomarker, and FDA approval in combination with pertuzumab.

Clinical progress was accompanied by commercial expansion. Large pharmaceutical companies continued to invest heavily in ADC development, while regulatory approvals broadened the range of cancers in which the drugs could be used.

Twenty-five years after the first ADC was approved, the field looks markedly different. More than a dozen conjugates are now available across haematological malignancies and solid tumours, with hundreds more in development. Moreover, current research is looking for ways to refine the approach by identifying the right patients, understanding resistance, reducing toxicity, and developing new payloads and linker technologies.