Emerging ADCs Target Elusive Solid Tumors

Innovations in antibody-drug conjugates (ADCs), encompassing new payloads and targets, are set to be highlighted at the American Association for Cancer Research's annual gathering in San Diego. Companies such as Elevation Oncology and Tubulis are anticipated to unveil fresh findings from their ongoing projects.

ADCs have evolved significantly since the first was approved by the FDA nearly a quarter-century ago for the treatment of acute myeloid leukemia. Initially, these therapies were primarily for blood cancers, but they have now become potent options for solid tumors. David Dornan, Chief Scientific Officer at Elevation Oncology, points out that solid tumors present a unique challenge due to their epithelial cell nature and resistance to multiple drugs. Currently, six out of eleven ADCs available are designed for solid tumors, and the next wave of development is focusing on the most difficult cancers to treat.

Nathan Tumey, an associate professor at Binghamton University, notes a shift in focus from liquid tumors to solid ones in the ADC field. The current generation of ADCs combines monoclonal antibodies with potent cytotoxic compounds, connected by a stable linker. With the ADC market projected to reach $30 billion by 2028, there is significant investment in refining these components.

Jake Van Naarden, president of Eli Lilly’s Loxo Oncology, indicates that the field is transitioning from the second to the third generation of ADCs. The first generation lacked sophistication in payload classes and other factors, while the second generation is more intentional, considering the payload class, chemotherapy type, and the pursuit of a bystander effect.

A novel class of payloads gaining attention is topoisomerase inhibitors, which have shown a broader therapeutic window compared to the previously common microtubule inhibitors. Tumey highlights the success of Enhertu, a therapy approved in 2019 for HER2-positive breast cancer, which has spurred excitement in this area.

AstraZeneca and Daiichi Sankyo are working on a new TROP2-targeted ADC, datopotamab deruxtecan (Dato-DXd), which has received FDA consideration for second-line non-small cell lung cancer and hormone receptor-positive, HER2-negative breast cancer.

The development of ADCs with dual payloads is also on the horizon, offering a variety of options for patients. Dornan suggests that dual payloads could become a new trend in ADCs, targeting different antigens or combining multiple payloads with different mechanisms.

Beyond payloads, linker technology and cleavability are crucial in the development of successful ADCs, as is the molecule's ability to induce a bystander effect. Kristin Bedard of Loxo Oncology emphasizes the importance of linker stability to address the issue of treatment response duration due to severe side effects.

Dominik Schumacher of Tubulis highlights the potential for ADCs to improve response duration, with his company's platform focusing on flexibility in ADC design to achieve long-lasting delivery of payloads to tumors.

Despite advancements, there remains a significant need for effective treatments for certain solid tumors, such as colon, pancreatic, and gastric cancers. Companies like Elevation Oncology are working on ADCs targeting these difficult indications.

The field of ADCs is poised to play a crucial role in improving outcomes for patients with solid tumors, although it is acknowledged that a diversified approach is necessary to fully address the complexity of cancer biology.