PharmTech: Advancing ADCs to the Next Level

Featured Moderator: Nicolas Camper, Senior Director of Bioconjugation Chemistry

Following a long road to success with antibody-drug conjugates (ADCs), developers today are seeing regulatory approvals for ADCs as a more common occurrence. Better success in the current environment is largely due to technology improvements that have helped minimize risk and enhance therapeutic efficacy for these complicated drugs. However, the manufacturing of ADCs remains a complex process, involving requirements for both the large-molecule and small-molecule components. The linker technology joining the two pieces also has its own requirements. Because of their manufacturing complexity, ADC development and production increasingly requires outsourcing services.

Three major challenges for drug developers trying to bring ADCs to market include lack of capacity, lack of expertise in scaling up, and the complexity of the supply chain, notes Christian Morello, vice-president and head of the Bioconjugates Business Unit at Lonza.

In looking at the overall dynamic of innovation in the ADC space, the majority of innovation is coming from small biotech companies, and those companies are not necessarily well equipped with the internal capacity to produce the product, Morello points out. “There is also a lack of knowledge about the industrialization and the scale up of ADCs,” he says. “And [there is also] the complexity of the supply chain; Indeed [we] within the bioconjugate field, we are bringing different pieces, like a puzzle, to produce the drug substance. It implies [much] complexity [and requires] management of different sourcing in order to make it happen.”

These challenges are what ADC developers have to face and overcome to produce clinical supply or commercial supply, Morello emphasizes. “This is where CDMOs [contract development and manufacturing organizations] bring a lot of benefit, because we have [experience with] different modalities. [Especially at Lonza,] we’re totally integrated, so we offer fully integrated services to make it happen and to accelerate [the developer’s] path to commercialization,” Morello says.

Unique requirements

ADCs have unique manufacturing requirements, which is part of their complexity. “With ADC specificity, we are merging two worlds,” explains Morello. “We are merging the water and the solvent, the biologic and the chemistry. So, with this integration of two worlds, it requires specific skills.” Morello also cautions carefulness when dealing with the risks associated with the chemistry involved in ADC manufacture. “You need to take care about potential explosion or flammable risk associated [with] the chemistry, but you also need to take care about the potential contamination due to microbes if you’re not working with adequate procedure for clean environment. So, the operating model is very specific.”

The science of ADCs has evolved significantly over the past 20 years, Morello also points out. Many improvements can be seen in the carrier component (protein or peptide), the linker component, and the payload, all of which makes the conjugation technology more complex.

“There have been a lot of new developments in terms of congregation and linker technologies,” agrees Nicolas Camper, senior director, Bioconjugation, at Abzena. “There is a definitive move towards site-specific conjugation technologies and away from stochastic conjugation approaches that allows [us] to prepare better-defined antibiotic-[drug] conjugates,” he says.

Camper also points out another new development that he’s observed over the past few years, which is that linker technology is becoming more sophisticated. “Quite often, when you conjugate cytotoxic drugs, they are quite hydrophobic, and that can impact the performance of your ADC. So, there has been a lot of effort put into developing more hydrophilic linkers,” he explains.

Another noticeable advancement has been in the development of branch linkers. These branch linkers give some options for preparing the ADC and modulating the drug loading. “[T]hat is something relatively new and should have an impact on the performance of ADCs and ultimately result in better ADCs and more programs,” he says.

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