Opportunities and challenges from the rise of antibody drug coagulates

Antibody drug coagulates (ADCs) are an inherently complex, fast-moving field of oncology. They present both exciting treatment opportunities and difficult challenges in terms of drug resistance, adverse effects, and stakeholder education. Will Fazzone, SVP Scientific Services at Nucleus Global, an Inizio Medical, takes a look at ADCs’ revolutionary rise and the part medical communications can play in their success.   

From a drug development standpoint, ADCs are unique; the result of two streams of research stretching back over more than a century. Firstly, we had the ground-breaking advances in chemotherapy and payload technology, which included the identification of topoisomerase (Top1) inhibitors. Secondly, we’ve had monoclonal antibodies, which have seen considerable advancements over the past 50 years, including the approval of trastuzumab for the treatment of HER2-positive breast cancer. 

These two treatment approaches came together through advances in medicinal chemistry in the early 2000s to bring about the era of ADCs, with a large number of approvals across various solid and hematologic cancers occurring over the past decade.  

Pushing the boundaries  

Since then, ADCs have continued to push boundaries through technological advancements, leading to improvements in patient outcomes. We now know for instance, that specific characteristics of the monoclonal antibody, such as subclass, can influence key aspects, including immunological effects, as well as half-life.  

As for the payload, ADCs allow for efficient delivery of a very potent cytotoxic agents to be efficiently delivered. These typically wouldn’t be tolerated by the body if administered as systemic chemotherapy. Advances in linker technology including the development of cleavable linkers allow for the release of the payload with the potential for spread beyond the target tumor cell into the surrounding microenvironment. This can elicit bystander effects, which have driven innovation in, the treatment of breast cancer as well as other tumor types. 

We recently saw data presented for the DESTINY-Breast06 study, which evaluated trastuzumab deruxtecan – a HER2-targeted ADC with a Top1 inhibitor payload that can elicit bystander effects. The study compared trastuzumab deruxtecan against physician’s choice chemotherapy in patients with previously treated hormone receptor positive HER2 low and ultra-low metastatic breast cancer (MBC). This is a group of patients that historically would have been classified as HER2 negative and not too long ago wouldn’t have received HER2-targeted therapy. 

We already know from other trials that HER2 low MBC can benefit from trastuzumab deruxtecan. But this study was unique in that it also included the HER2 ultra-low patient population, characterized by tumors with faint HER2 staining on a very small fraction of cells. 

Looking at the results, we can see positive outcomes across each group of patients, including the HER2 low and ultra-low. Overall, the data demonstrates the continued transformative potential of ADCs and how they alter breast cancer treatment.  

Adverse events and treatment resistance 

That’s not to say there aren’t challenges with this treatment and with ADCs more broadly. And this is where MedComms can play an important part.  

One of these challenges is in further defining the patient population to inform how these data can be optimally incorporated into the landscape. So, for trastuzumab deruxtecan, refining HER2 cutoffs and potentially incorporating additional biomarkers will help to drive the identification of patient subsets. These may also be influenced by other clinical factors such as prior treatments, risk for adverse events, and even patient preferences.

ADCs are associated with unique adverse events that are often attributable to the payload. Interstitial lung disease remains a challenge for trastuzumab deruxtecan, while other unique ADC side effects include ocular toxicity and dermatologic toxicities, among others. 

There’s a clear role here for MedComms to address these challenges including helping shape understanding of management strategies for adverse events and increasing awareness around patterns and mechanisms of treatment resistance. These strategies should be directed to all key stakeholders including physicians, allied health professionals, and patients. 

One of the most complex challenges facing drug development teams is gaining a deeper understanding of treatment resistance to ADCs. This can arise through mechanisms related to individual components, such as binding of the monoclonal antibody or increased efflux of the payload. 

Developing educational solutions 

Despite these difficulties, ADCs are going to continue having a transformative impact in oncology and are already being rapidly incorporated into treatment algorithms, not only for solid tumors but for hematologic cancers as well. 

At Inizio Medical, we’re well placed to work with pharma and biotech companies in this space, helping them overcome these challenges and develop educational solutions that maximize patient outcomes.