Antibody drug conjugates (ADCs) are a big deal in oncology. And rightly so: they combine highly specific targeting with a potent cytotoxic payload to deliver tremendous results. Since the approval of the first ADC in 2000, Mylotarg® for adults with acute myeloid leukemia (AML), ADCs have continued to make waves – something we can honestly say has revolutionised the way we approach oncology. Right now there are 15 approved ADC drugs for cancer indications, with reported hundreds more ADC candidates in pipelines or clinical trials,1 testament to the extensive interest and promise of this therapeutic approach.
But we have to ask, why have they been so successful where small molecules haven’t? What drives their success and potentially limits their efficacy? And what challenges still have to be overcome?
A Quick ADC Track Record
Despite their current success, ADCs’ adoption was a little slow to start. Interestingly, the complexity of ADC design, the combination of a cytotoxic drug, an antibody, a linker, and of course the conjugation technology, was both the core of its success and the main reason it took so long for the field to initially take off. ADC developers had to wrestle with early issues such as the lack of stable conjugation methods, limited therapeutic profiles, and poorly designed linkers. However, advances in our understanding of selectivity, site-specific conjugation, and improved stability have led to this area of R&D thriving like it is.
Over the past two years, the ADC industry has witnessed significant milestones. A few of the most notable achievements include the approval of ADCs by the US Food and Drugs Administration (FDA), such as Elahere® (Mirvetuximab soravtansine) for ovarian cancer and Tivdak® (Tisotumab vedotin) for cervical cancer. We’ve also seen investment from big pharma into smaller biotech ADC companies that has brought not only a hefty dose of confidence but also a host of promising prospects to the field.
If we look at the R&D side of things, we’ve seen marked improvements in linker and conjugation chemistries that translate into clinical successes – you can see this in action when you take a look at Enhertu® (Trastuzumab deruxtecan), which is the first HER2-directed therapy for patients with HER2-low metastatic breast cancer to be approved in the EU.2 Enhertu® was developed with a novel linker–payload combination (a tetrapeptide linker and an exatecan derivative as a payload), which makes it so effective in the treatment of many HER2-positive cancers.3
ADCs have a great track record, and with next-generation ADCs coming onto the scene, they look to be going from strength to strength. But what makes them so successful?