Inside Precision Medicine‘s Editor in Chief Damian Doherty spoke with Sue McPherson, Executive Director, Client Affairs at WuXi AppTec, about her path into toxicology, the evolving needs of sponsors, and what it takes to run successful preclinical programs today.
Damian Doherty: Sue, thank you for joining me. I know you’ve recently referred to moving “Beyond the Magic Bullet” when talking about the evolution of Antibody-Drug Conjugates, or ADCs. Can you elaborate on what you see as the core innovations bringing this vision to life today?
Sue McPherson: Absolutely, Damian. The fundamental idea of a targeted therapy has been around for ages, but realizing that vision in ADCs comes down to molecular precision in three key areas: the antibody, the linker, and the payload. We’re seeing strategies like site-specific conjugation ensuring uniform drug-to-antibody ratios, which is a huge step forward. Then there are significant improvements in linker chemistries, making them much more stable in systemic circulation. And finally, the development of ultra-potent payloads, often with built-in features for bystander killing, truly enhances their efficacy. Together, these innovations are helping ADCs achieve better therapeutic indices while reducing off-target toxicities.
Damian Doherty: That makes sense. Let’s break down those components a bit. Starting with the antibody, it acts as the “homing device.” What are some approaches to optimize its role in terms of safety and efficacy?
Sue McPherson: The antibody focuses on high specificity and rapid internalization properties. The goal is to maximize payload delivery precisely to the tumor cells, ideally those expressing the target antigen predominantly or even exclusively. This selective targeting is crucial to minimizing off-target effects and maximizing the therapeutic impact where needed most.
Damian Doherty: You mentioned the linker’s critical role in stability. Can you explain the difference between cleavable and non-cleavable linkers and how advancements address systemic toxicity?
Sue McPherson: Historically, premature payload release from the linker in the bloodstream was a major contributor to systemic toxicity. Cleavable linkers, such as acid-labile or protease-sensitive, are designed to release the payload specifically within the tumor cell, where conditions are right. Non-cleavable linkers, on the other hand, rely on cellular catabolism for payload release. The recent advances in linker technology have centered on improving the stability of both types in systemic circulation, drastically reducing premature release and consequently, off-target effects.
Damian Doherty: Moving to the payload, these are often incredibly potent. What new classes of payloads are being incorporated, and what are the benefits of these more modern approaches, particularly concerning bystander killing?
Sue McPherson: The trend is towards ultra-potent payloads, capable of inducing cell death at sub-nanomolar concentrations. We’re seeing new classes like topoisomerase inhibitors being widely adopted. What’s particularly exciting about some of these newer payloads is their ability to promote “bystander killing.” This means that even if not every single tumor cell is directly targeted by an ADC, the released payload can still affect neighboring tumor cells, enhancing the overall efficacy and improving tumor eradication. These payloads often act by disrupting key cellular machinery—topoisomerase inhibitors, for instance, interfere with DNA replication, while other classes, like auristatins and maytansinoids, disrupt microtubule dynamics. Many of these agents are designed to be active at sub-nanomolar concentrations. When incorporated into ADCs, they can also support bystander killing, meaning that even tumor cells not directly targeted by the ADC may be affected by the locally released payload.
Damian Doherty: Design is obviously a key piece, but as we know, it can’t be looked at in isolation. This brings us to toxicology. Why are traditional safety studies often insufficient for ADCs, and what unique considerations must developers account for?
Sue McPherson: That’s a critical point, Damian. The complexity of ADCs means you can’t just apply standard safety studies for biologics or small molecules. You must consider the unique behavior of the entire conjugate, the unconjugated antibody, and the free payload, all separately and in concert. Each component can have its own toxicity profile. For instance, if prematurely released, the unconjugated antibody might have off-target binding, or the free payload can cause systemic toxicity. So, a holistic approach is essential, including specialized toxicokinetic profiling to track the intact ADC, total antibody, and free payload concentrations.
Damian Doherty: That sounds like a significant bioanalytical challenge. What are some key hurdles you’ve seen in toxicology studies for ADCs, particularly concerning variability in drug-antibody ratios or immunogenicity?
Sue McPherson: You’re absolutely right. The bioanalytical challenges are substantial. Variability in drug-antibody ratios, or DARs, can lead to heterogeneous products with unpredictable safety profiles. Then there’s the challenge of quantifying free payload accurately, which is vital for understanding systemic exposure and correlating it with observed toxicities. And of course, immunogenicity is a big one. The body can develop anti-drug antibodies against any part of the ADC—the antibody, the linker, or the payload. Robust bioanalytical methods are indispensable, including ligand-binding assays for intact ADC and total antibody, and LC-MS-based assays for free payload. We also need to perform anti-drug antibody screening and domain-specific immunogenicity evaluations to truly understand the risk profile before clinical translation.
Damian Doherty: Regulatory expectations are often a moving target, especially for novel modalities like ADCs. How are developers navigating this, and what “weight-of-evidence” approach are agencies emphasizing?
Sue McPherson: Regulatory guidance for ADCs is still evolving, spread across various ICH documents and Q&As. This puts the onus on developers to build comprehensive, scientifically justified safety packages. The “weight-of-evidence” approach is key here. Agencies are favoring flexibility and a robust scientific rationale over rigid, one-size-fits-all requirements. This places added responsibility on developers during IND-enabling studies. In addition to expanded toxicokinetic profiling—measuring intact ADC, total antibody, and free payload—they need to tailor supplemental studies based on the payload’s mode of action. That might include genotoxicity, immunogenicity, or phototoxicity testing. The emphasis is on aligning each component of the study design with the intended clinical use and ensuring the rationale is scientifically robust. Early engagement with regulators and aligning the study design with the intended clinical use are absolutely essential to streamline the path to approval.
Damian Doherty: Finally, Sue, how do all these elements—targeted design, nonclinical rigor, and precise evaluations—ultimately work together to widen the therapeutic window for ADCs? What’s the roadmap for innovators looking to lead the next wave of targeted oncology breakthroughs?
Sue McPherson: It’s truly an integrated approach. When you combine smart design, like site-specific conjugation for uniform DARs and stable linkers to minimize premature payload release, with rigorous preclinical testing and sophisticated bioanalysis, you significantly widen the therapeutic window. This means more drug gets to the tumor with less collateral damage to healthy tissues.
Precise pharmacokinetic and immunogenicity evaluations are also critical here, measuring intact conjugate, unconjugated antibodies, and free payloads, and understanding any anti-drug antibody responses. The roadmap for innovators is clear: embrace this integrated approach. Leverage molecular engineering innovations alongside predictive safety science. By mastering both design and nonclinical strategy, ADC innovators can move beyond the conceptual “magic bullet” and deliver on the promise of more effective, targeted, and safer cancer therapies. This is how we’ll drive the next wave of breakthroughs in oncology.
Damian Doherty: Sue, this has been incredibly insightful. Thank you for sharing your expertise.
Sue McPherson: My pleasure, Damian. Thank you for the opportunity to discuss these innovations.
Sue McPherson joined WuXi AppTec in 2011 and brings more than 30 years of global toxicology experience to her role as Executive Director, Client Affairs. Before joining WuXi AppTec, she worked at Charles River Laboratories (Montreal), where she was a Study Director in general toxicology and reproductive toxicology, and later moved into program management. In addition to her role as WuXi AppTec’s Executive Director, Toxicology, she oversees the Study Director team that performs in-life toxicology studies and provides technical support for toxicology programs.
