Guest editorial by Pedro Valencia, PhD, Vice President, Asset Strategy Leadership, Oncology, AbbVie, and Christian Maurer, Vice President, Manufacturing, AbbVie
Antibody-drug conjugates (ADCs) have emerged as a key treatment class in oncology with the potential to replace conventional chemotherapy across many tumor types. ADCs remain a major focus of research and development (R&D) as new technologies and approaches continue to drive innovation in the field. However, the journey of bringing ADCs to patients is a complex, multi-step process spanning scientific discovery, clinical development, manufacturing, and operational execution.
Considerable scientific resources and expertise have gone into engineering ADC candidates that are both effective and safe — with the broader goal of offering patients alternatives to traditional chemotherapy across many cancer types.
At the scientific discovery and clinical development stages, teams across the field have been hard at work designing ADCs with highly stable linkers and optimizing drug-to-antibody ratios to enhance the therapeutic index and reduce off-target effects. Deepening our understanding of tumor biology and selecting the right targets remains central to improving patient outcomes.
Beyond the scientific challenges of developing ADCs, manufacturing feasibility is an equally critical and deeply intertwined dimension of the R&D process. These are not sequential hurdles; decisions made at the bench have direct consequences on what can be produced at scale. As the modality matures, the field must simultaneously advance the science and implement the operational strategies needed to manufacture these complex therapies efficiently, safely, and at scale.
The fundamental design elements of an ADC, including target biology, payload selection, linker stability, and translational evidence, also shape critical operational considerations. These factors determine whether a program can transition into high-potency manufacturing environments, scale reliably, and consistently meet regulatory and quality expectations without unnecessary delays or complexity.
Translational evidence as a key to strategic ADC manufacturing
Given the inherent complexities of establishing ADC programs, achieving readiness for distribution upon asset approval may take several years. This lengthy process leaves little margin for error.
Successful manufacturing strategies for ADCs are grounded in translational understanding of clear target expression, internalization dynamics, and precise alignment between the specific biological mechanism and selected payload. This foundation enables a more predictable development pathway, informing expectations around clinical parameters such as drug-to-antibody ratio control, hydrophobicity and aggregation risks, stability characteristics, and critical quality considerations.
A clear understanding of how the ADC is expected to perform within the tumor microenvironment further informs operational needs — from containment strategies to stability assessments and long-term process plans.
Early data and emerging hypotheses around potential resistance mechanisms can also guide key manufacturability considerations. When these translational insights align and bridge preclinical models into early clinical signals, manufacturing partners can establish realistic production parameters, anticipate process sensitivities, and design analytical packages that support long-term development strategy for the ADC.
Lessons from early ADCs informing next-generation development
The approved first-generation ADCs have generated a body of operational and translational knowledge that is now actively reshaping how next-generation programs are designed and manufactured. Critically, these lessons are most valuable when applied early during discovery and preclinical development, before manufacturing complexity becomes difficult or costly to reverse.
Linker chemistry offers one of the clearest examples of this feedback loop. Early programs revealed that linker instability is not merely a manufacturing inconvenience — it is a signal of deeper R&D design risk. Linker systems that demonstrate stability in vitro may release the payload prematurely under physiological stress, with consequences for both efficacy and safety. This has driven R&D teams to prioritize linker validation under conditions that more closely replicate patient exposure, and raise the bar for what constitutes an acceptable preclinical candidate.
Aggregation, the tendency of ADC molecules to clump together, similarly reflects lessons learned from earlier programs. When ADC molecules aggregate, they can trigger out-of-specification results in which the drug fails to meet pre-defined quality and purity standards, as well as clinical tolerability problems. This makes aggregation a meaningful indicator of both product quality and patient safety.
Translating science into scalable manufacturing
Achieving success in ADC manufacturing partnerships demands an evidence-based translational rationale, a manufacturability strategy attuned to the inherent complexities of high-potency therapeutics, and an operational model capable of delivering at scale.
The most successful ADC programs demonstrate continuity from biology-driven development to industrial implementation, enabled by disciplined decision-making throughout. By thoughtfully integrating payload and linker design with critical R&D factors such as antigen density, internalization dynamics, tumor heterogeneity, and resistance biology, teams can engineer constructs that perform well in early studies and translate efficiently into scalable manufacturing processes.
Early, deliberate interventions inform this continuity — from discontinuing constructs prone to aggregation at scale, to re-engineering linkers shown to be unstable under physiological stress. These are the kinds of R&D decisions that directly determine the smoothness of downstream manufacturing operations and reduce the risk of costly late-stage disruptions.
As demand for ADCs grows and innovation expands into new targets and payload classes, organizations that couple early translational insights with rigorous operational execution are well-positioned to deliver sustained benefits to patients.
Institutionalizing this integration between biology and CMC not only accelerates development timelines but builds meaningful competitive advantage in an increasingly crowded landscape. Advances in bioconjugation platforms, containment systems, and process technologies are expanding what is possible in ADC manufacturing, enabling the industry to keep pace with scientific innovation.
Ultimately, advancing ADCs from initial discovery to patient delivery requires coordinated expertise across scientific, technical, regulatory, and operational domains. Success depends on thoughtful target selection, advanced engineering, manufacturing practices grounded in translational science, comprehensive clinical development, and uncompromising operational rigor.
Pedro Valencia, PhD is Vice President of Asset Strategy Leadership, Oncology at AbbVie, where he oversees the lifecycle of oncology assets across the company’s solid tumor and blood cancer portfolio. He holds a PhD in chemical engineering from MIT and previously worked as a Principal at The Boston Consulting Group.
Christian Maurer is Vice President of Small Molecules Manufacturing at AbbVie. He has spent over six years in senior manufacturing leadership roles across AbbVie’s global network, most recently serving as Site Head in Worcester, Massachusetts, where he led a significant operational transformation of the site’s biologics and ADC manufacturing capabilities.
References
Maecker H, Jonnalagadda V, Bhakta S, et al. Exploration of the antibody–drug conjugate clinical landscape. mAbs. 2023;15(1):2229101. doi: 10.1080/19420862.2023.2229101.
