Opinion: The Next Generation of ADCs Will Improve Cancer Treatment

In recent years, the field of antibody-drug conjugates has seen a resurgence in research and clinical development efforts, driven in large part by the clinical benefit provided to cancer patients treated using this novel therapeutic approach. After decades of technological advancements and learnings that have helped us better understand these complex molecules, ADCs have now entered their golden age, with the field energized to broaden the responsive patient population, enhance the sustainability of therapeutic responses, and, equally important, improve their tolerability.

That’s why we at Zymeworks and others in the ADC space are now working to develop a new generation of these promising cancer therapeutics

ADCs represent a significant advance in therapeutic engineering. They combine an antibody, a linker or conjugation method, and a payload into a single molecule for delivery to a specific target. Building on the successful development of the first approved ADCs (Adcedtris, Kadcyla, Mylotarg and Besponsa), a total of eight ADCs were approved by the FDA between 2019 and 2022. These approvals represent important advances in the treatment of both liquid and solid tumors using a range of payload mechanisms with varying potency.

But many current ADC-based treatments are associated with high discontinuation rates, especially those with the more established payload classes such as auristatins, maytansinoids and pyrrolobenzodiazepine (PBD) dimers. Another payload class that has emerged in recent years and represents a promising alternative in the treatment of several types of cancer is camptothecins. There are currently two approved camptothecin ADCs, Enhertu (trastuzumab deruxtecan) and Trodelvy (sacituzumab govitecan). While data has shown that they provide significant therapeutic benefit for patients with different types of cancer, camptothecin ADCs can present limitations and exhibit severe toxicities such as neutropenia, anemia, interstitial lung disease and gastrointestinal effects.

Emerging clinical data suggest that treatment-related off-target toxicities and maximum tolerated doses in patients are primarily related to ADC payloads. By contrast, the efficacy of ADC-based treatments, especially for solid tumors, is likely driven by a complex combination of targeted payload delivery, free payload exposure and tumor sensitivity to the molecule’s components. ADC features (including conjugation and drug-linker designs) and target expression may influence sites and rates of ADC disposition, and thus tumor, tissue and systemic exposure to the payload. It is essential that researchers consider and optimize all ADC payload properties—including the target, antibody, linker, and payload itself—to maximize clinical efficacy while balancing the risk of toxicities.

Existing camptothecin ADCs have limitations, but their clinical successes have sparked a renewed interest in the development of alternative therapies in this class. For example, researchers at Zymeworks recently prepared and assessed a panel of camptothecin analogs in vitro, with different substitutes at the C-7 and C-10 positions of the camptothecin core. They also selected different linker compounds spanning a range of potency and hydrophilicity, elaborated them into drug linkers, conjugated them to trastuzumab and evaluated them in vitro and in vivo. Together these assessments were used to determine the optimal properties of a potential next-generation ADC candidate.

The findings, published recently in Molecular Cancer Therapeutics, identify a novel camptothecin analog that, upon conjugation to different tumor-targeting antibodies via a clinically validated MC-GGFG-based linker, demonstrated robust anti-tumor activity in mouse models of multiple tumor types and tolerability in nonhuman primates. The unique design of the novel drug candidate selected (ZWD06519) supported the desired properties of moderate payload potency, low hydrophobicity, strong bystander activity, robust plasma stability and high-monomeric ADC content. Together, these favorable attributes have the potential to better balance efficacy, safety and tolerability and improve cancer treatment for many patients.

As drug developers explore innovative technologies and strategies in oncology therapeutics, the widespread interest in ADCs is likely to continue to grow. There are significant opportunities to improve the design of existing ADCs, given the complexity of these molecules and the potential to modify each component in a variety of ways to achieve an optimal safety and efficacy profile while minimizing off-target effects. To increase the likelihood of success, researchers must have access to a toolbox of technologies to carefully select the antibody, linker and payload and to refine each ADC design feature. Furthermore, it is critical to continue incorporating learnings from the clinical development of existing ADCs—both successful and unsuccessful—to better understand each ADC component, the role it plays, and how the pieces can work together in an integrated design.

Taken together, advances in technology and improved mechanistic understanding of ADCs pave the way to optimizing their efficacy and tolerability not only in the context of monotherapy, but also as a component of combination therapy alongside complementary cancer treatments such as immunotherapy, targeted therapy and traditional chemotherapy. Ultimately, the coordinated design and optimization of ADCs holds the promise of providing unprecedented clinical benefit to patients who are unserved by existing therapeutic options, affording the best possible chance of a positive outcome.

Paul Moore, PhD, is chief scientific officer at Zymeworks, Inc. He has more than 25 years of U.S.-based experience in biologics drug discovery and development in biotechnology research. His career efforts have led to the discovery and development of a range of FDA-approved and clinical-stage biologics for patients with difficult-to-treat cancers and autoimmune conditions.