Antibody-drug conjugates (ADCs) are among the most promising innovations in cancer treatment today, combining the targeting precision of monoclonal antibodies with the potent killing power of cytotoxic drugs. In a recent webinar hosted by The START Center for Cancer Research (“START”), a distinguished panel of oncologists and researchers explored the science, challenges, and future directions of ADCs.
Moderated by Dr. Manish Sharma, medical oncologist and co-director of clinical research at START Midwest in Grand Rapids, Michigan, the discussion featured experts Dr. Justin Call from START Mountain Region in Utah, Dr. Austin Duffy from START Dublin in Ireland, and Dr. David Quinn, executive medical director at AbbVie. This recap highlights the key takeaways from the conversation, offering a snapshot of where the field of ADCs stands today.
The ABCs of ADCs
The discussion began with an essential overview of ADC architecture structured around the three key components: antibody, linker, and payload.
Dr. Austin Duffy, Director of Research at START Dublin, outlined critical considerations in target selection, emphasizing the importance of examining tumor expression patterns, biological relevance, and expression levels both across different cancer types as well as different stages within the same cancer type. He also highlighted additional considerations in target selection, including the relevance of the target molecule to underlying tumor biology and the potential for combination therapies.
Dr. David Quinn, Executive Medical Director in Oncology Early Development at AbbVie, highlighted the strategic importance of linker technology. “The linker is often overlooked but its makeup is very important,” he noted, saying that an ideal linker should release the payload into or close to the target cell. Releasing the payload into the blood or at off target locations can result in toxicities. He noted how advances in linker technology have improved the therapeutic profile of newer ADCs.
Dr. Justin Call, Director of Clinical Research at START Mountain Region, provided insights into payload development, explaining that current FDA-approved ADCs utilize two main payload classes: microtubule inhibitors like derivatives of maitansine or maytansine, and DNA damagers like calychomycin, DXd and SN-38. Noting that while current payloads are cytotoxic, Dr. Call highlighted ongoing developments including immune-stimulating agents and protein degraders as alternative payloads.
Strategic Development Considerations
Target Expression: The panel extensively discussed optimal target expression requirements, illustrating the challenges and open questions by contrasting experiences with two recent trials. The panel highlighted the groundbreaking success of trastuzumab deruxtecan (T-DXd), which was initially approved for tumors with high HER2 expression, but later was shown in the DESTINY-04 trial to be effective even in patients with low levels of target expression, thereby significantly expanding the number of potential patients who could benefit. This success challenges conventional wisdom about required expression and, as shown in the CNS responses, questions the relative contributions of free versus bound payload.
Conversely, Dr. Duffy referenced the folate receptor experience in ovarian cancer, where an initial phase 3 trial requiring 50% expression proved negative, but whose exploratory analyses led to a subsequent positive trial focusing on patients with 75% expression. This dichotomy illustrates the difficulty of predicting optimal expression thresholds and generalizing expression levels, especially considering potential loss of antigen expression as tumors evolve.
The panelists all agreed that while understanding target expression is crucial, there are multiple factors influencing efficacy, including the linker, the chemical nature of the payload, the drug to antibody ratio and the bystander effect.
The discussion also covered the critical role of drug-to-antibody ratios (DAR) in ADC development. Dr. Quinn detailed their approach to DAR optimization: “We usually go between a DAR 2 and a DAR 6,” explaining how preclinical experiments inform these decisions. The panel noted that optimal ratios must balance payload delivery with molecular stability and tumor penetration.
Trial Enrollment: With limited understanding of the impact of target expression, the panelists agreed that enrolling a spectrum of patients with different expression levels in their tumors and deciding on the desired target expression levels based on retrospective analysis of efficacy may be the optimal way forward.
“I think based on the track record of ADCs, in my opinion, that seems to be the best way to avoid eliminating potential tumors or a protein expression that might actually benefit from the treatment,” noted Dr. Call.
Dr. Quinn provided the industry viewpoint, noting “when we’re designing these trials from the industry perspective, we’ve sometimes got competing agendas with the precision medicine folks saying select a group of patients with high expression. But that assumes that your marker is accurate, and can be turned around in a clinically acceptable timeline, which is a big ask logistically.”
He also noted that the industry is moving towards designing antibodies with a broader target population, including a next generation folate receptor antibody currently in clinical trials.
Drug Toxicity in ADCs – Promise vs Reality
A frank discussion of ADC safety profiles revealed both progress and ongoing challenges. While current ADCs haven’t achieved the initial vision of dramatically reduced toxicity compared to conventional chemotherapy, the panel noted significant advances in managing specific side effects and optimizing therapeutic windows.
Dr. Duffy offered a candid perspective: “If you brought the pioneers of ADCs forward in a time machine, they’d be amazed at how far we’ve come. But I think they’d also be surprised—and maybe disappointed—by how much toxicity remains part of the conversation.”
Dr. Call highlighted the fundamental challenge that many targets in solid tumors are “tumor-associated” rather than “tumor-specific,” making it difficult to completely avoid effects on normal tissues. Despite these challenges, the experts agreed that growing experience with ADCs has led to better toxicity management strategies and optimization of dosing approaches.
Dr. Quinn offered a slightly more optimistic perspective, highlighting improvements in newer generations of ADCs and the increased understanding of identifying MTD in ADCs. He emphasized the importance of Project Optimus in optimizing dosing strategies to balance efficacy and tolerability.
Q&A
The Q&A session addressed key technical aspects of ADC development. When asked about antibody fragments versus full-length antibodies, Dr. Quinn highlighted their potential for better specificity and immune modulation. The discussion also covered fractionated dosing strategies, which the panel noted are primarily guided by pharmacokinetic data rather than preclinical models.
Questions about the ADCs’ bystander effect on immune cells revealed dual mechanisms: while ADCs can deplete some immune cells, they also trigger beneficial immunogenic cell death. Dr. Duffy noted that since many ADC-treated patients have “cold” tumors, the elimination of suppressive immune cells might be advantageous. Additionally, the antibody component of ADCs can itself stimulate immune responses, suggesting potential synergies with immunotherapy approaches.
On linker stability, Dr. Quinn emphasized that while current technology is sufficient, continued improvement remains crucial for advancing next-generation ADCs, particularly those with dual-targeting capabilities.
The Road Ahead for ADCs
The panel concluded with a discussion of regulatory considerations and development strategies. Dr. Quinn emphasized the importance of industry-investigator collaboration and regulatory guidance, particularly regarding Project Frontrunner, in advancing perioperative and combination approaches.
The experts agreed that while significant progress has been made in ADC development, particularly over the past five years, substantial opportunities remain for optimization and innovation.
The experts identified several promising developments that could shape the future of ADC therapeutics:
- Bispecific ADCs targeting multiple antigens to address tumor heterogeneity
- Innovation in payload technology, including non-cytotoxic options
- Strategic combination approaches, particularly with immunotherapy
- Novel trial designs, especially in neoadjuvant and adjuvant settings
Dr. Quinn shared an optimistic industry perspective on emerging technologies, including glucocorticoid receptor modulators and other non-cytotoxic payloads. Dr. Duffy advocated for expanded clinical trial designs, particularly emphasizing the potential of window-of-opportunity trials in aggressive cancers like pancreatic cancer.
As the field continues to evolve, these advances promise to expand the therapeutic potential of ADCs in oncology. This momentum, coupled with growing industry investment and clinical experience, positions ADCs as an increasingly important tool in the future of cancer treatment.
To listen to the full broadcast of this webinar, click here.
About START
Deeply rooted in community oncology centers globally, The START Center for Cancer Research provides access to specialized preclinical and Phase 1 clinical trials of novel anti-cancer agents. START clinical trial sites have conducted more than a thousand Phase 1 clinical trials, including for 43 therapies that were approved by the FDA. START represents the world’s largest roster of Principal Investigators (PIs) across its eight clinical trial sites. Committed to accelerating passage from trials to treatments, START delivers hope to patients, families, and physicians around the world. Learn more at STARTresearch.com.
