Antibody-drug conjugates (ADCs) have emerged as one of the most promising modalities in oncology, offering a way to pair the targeting precision of antibodies with the potency of small-molecule drugs. But as interest in ADCs accelerates, so do the manufacturing challenges that stand between a promising construct and a clinic-ready therapy.
At the center of those challenges is conjugation—specifically, controlling how many drug molecules are attached to each antibody. Known as the drug-to-antibody ratio (DAR), this parameter plays a crucial role in an ADC’s safety, efficacy, and stability. “One of the primary challenges in developing ADCs is controlling the conjugation process and achieving a consistent drug-to-antibody ratio,” says Lisa McDermott, director of process and analytical development at MilliporeSigma, the U.S. and Canada Life Science business of Merck KGaA, Darmstadt, Germany.
Recent advances in site-directed conjugation chemistries have helped bring greater precision to DAR control, but they have not eliminated the need for deep process understanding. According to McDermott, consistent outcomes still depend on careful optimization of reaction parameters such as time, temperature, and reagent concentrations. “Even with site-directed technologies, delivering a consistent product requires thorough insight into how the antibody, linkers, and reagents interact,” she says.
To gain that insight, manufacturers are increasingly turning to reactors paired with statistical data analysis. These systems enable detailed interrogation of conjugation chemistry, helping teams fine-tune conditions to hit target DARs reliably. At the same time, specialized equipment—particularly single-use ADC reactors—has improved both efficiency and reproducibility, reducing variability that can arise during scale-up.
The field has also evolved upstream. Antibodies and targeting proteins are now being designed specifically with conjugation chemistry in mind, rather than adapted after the fact. That shift, McDermott notes, has made downstream processing more predictable and robust.
Scale-up remains another crucial hurdle, especially as programs move from development into GMP manufacturing. To address this, MilliporeSigma has invested in scale-down models that allow processes to be stress-tested before production. “We’ve developed a 10-L single-use scale-down model of our GMP platform reactors,” McDermott says, adding that the system has been evaluated for blend times, temperature control, and material compatibility. The goal is to “transition smoothly between development and multiple manufacturing scales while ensuring a robust process,” McDermott says.
Purpose-built, single-use ADC reactors will streamline that transition. Designed for rapid scale-up, these systems can significantly shorten timelines from development to commercial production. As McDermott puts it, efficient manufacturing templates don’t just simplify operations—they “accelerate the delivery of therapies to patients,” a priority as ADC pipelines continue to expand.
