Transformative Changes in ADC Development Over the Next Decade

From Paul Ehrlich’s original ‘magic bullet’ concepts, antibody-drug conjugates (ADCs) have undergone significant evolution over the years, yet it is only in the last 2 decades that we have seen them adopted as a therapeutic option. From early iterations to modern versions, the ADC field has strived to improve therapeutic windows and patient standard with good yet debatable outcome, targeting mechanisms, and payload efficacy. However, as we look ahead to the next ten years, it is clear that even more transformative changes are on the horizon. Here, we explore three major developments that are set to reshape the ADC landscape. 

1. Combination Therapy ADCs: Dual Payload Strategies 

One of the more interesting innovations in ADC development is the concept of combination therapy ADCs. In recent years, the idea of loading dual payloads onto a single ADC has gained traction. Combination cancer therapy approaches administer two targeted therapies separately, but the combined side effects of this co-administration can result in dose reductions and suboptimal therapeutic responses. Combination, dual payload, ADCs aim to circumvent this issue by delivering two synergistic drugs simultaneously to the target cells. 

The dual payload strategy might not only improve therapeutic efficacy but also reduces the risk of drug resistance, a common challenge in oncology. Furthermore, combination ADCs can be used, for example, to enable the integration of synergistic pathway inhibition, or the pairing of DNA damage agents with DNA repair inhibitors. This technique can enhance the effectiveness of treatment while minimizing systemic toxicity. The flexibility in choosing either a bifunctional linker or orthogonal attachment points on the antibody also allows for precise control over drug-antibody ratio (DAR), further optimizing therapeutic outcomes. We envision a key area of discussion in the future will be the employment of complementary payload MoAs, moving away from conventional cytotoxic, with the aim to minimise potential resistance pathways being adopted by the target.   

2. Beyond Oncology: Expanding ADC Applications 

Currently, ADCs are predominantly utilized in oncology, but in the next decade we expect to see the technology expand beyond cancer treatment. The potential of ADCs in non-oncology indications, such as inflammation and immunology, is becoming increasingly apparent. By moving away from cytotoxic payloads and exploring new modalities, ADCs are starting to target inflammatory pathways and deliver precision therapeutics to diseased tissues with minimal side effects. 

Another intriguing area is the potential application of ADCs in central nervous system (CNS) diseases. While molecules have struggled to cross the blood-brain barrier, some antibody-based therapies have shown surprising success. Understanding the mechanisms that enable this permeability could pave the way for CNS-targeted ADCs to treat neurodegenerative conditions and cognitive decline. 

3. Advancements in Conjugation

The third key development lies in conjugation technologies, traditional conjugation approaches often result in heterogeneous ADCs with variable DAR and pharmacokinetic profiles. However, innovative conjugation techniques are emerging that offer greater modularity and precision in payload attachment. 

By improving conjugation site selectivity and fine-tuning the hydrophobicity and hydrophilicity balance, we can now create ADCs with optimized stability, solubility, and targeted delivery. Additionally, advancements in linker chemistry allow for more controlled payload release and improved tissue penetration, which are critical for maximizing therapeutic efficacy. 

Holistic approach to ADC development

As the ADC field continues to evolve, these transformative changes promise to unlock new therapeutic possibilities and expand the utility of ADCs across diverse therapeutic applications. From combination therapy ADCs to non-oncology applications and enhanced conjugation technologies, the next decade will undoubtedly be marked by ground-breaking advancements. Embracing these innovations, in combination with the diverse expertise of multi-disciplinary research teams spanning both large and small molecule discovery, will not only improve patient outcomes but also redefine the ADCs of the future.

Catch up on the full ADC development blog series:

Part 1: Exploring new paths in ADC development

Part 2: What’s the Evolving Role of Medicinal Chemistry in ADC Development?

Part 3: Linker Technologies in ADCs: How They Impact Efficacy & Stability

Part 4: Toxicity & Efficacy in ADCs: How to Get it Right

About the Authors

Allan Jordan is Vice President Oncology Drug Discovery at Sygnature Discovery and Josh Greally is ADC Lead at Sygnature Discovery. Follow their ADC development series on YouTube to hear all their insights.