ADCs Reap the Benefits of Continual Research and Process Improvements

After early market failures, antibody drug conjugates (ADCs) have made a comeback in recent years. Innovations in technology and a better understanding of disease mechanisms have helped advance the development of ADCs. This success has been evidenced by the growing proportion of ADCs gaining regulatory approval.

Key contributing factors

ADCs remain an area of intense focus for many biopharma companies for good reason. The ability to specifically target diseased cells and spare healthy cells has been the quest for the biopharmaceutical industry as a whole and was not something that was thought to be a viable option in early days, according to Lisa McDermott, director of Process and Analytical Development (PAD) Global Contract Manufacturing Services, MilliporeSigma, the US and Canada Life Science business of Merck KGaA Darmstadt, Germany. Nowadays, the ability to see impact on patients even in Phase I studies in oncology brings an immediacy to ADC drug development that has kept it such an engaging field, she notes.

From a science perspective, developing ADCs should be approached in a collaborative way, where the best characteristics of both large and small molecules are combined, according to McDermott.

When developing a new ADC, there are a few key decisions that must be considered upfront. In the preclinical space, for instance, one needs to have deep knowledge about the target and have theories on how to address it. “Once you have identified a candidate that meets your target profile, then the ability to scale and control the process for producing enough material for clinical and commercial supplies is critical,” McDermott states.

“Once you start the CMC [chemistry, manufacturing, and controls] development, it is important to understand if your process is adaptable to existing templates, or if there is a need for a novel process,” McDermott adds. She also points out that using a contract manufacturing and development organization (CDMO) partner is wise because CDMOs that work on these platforms regularly will have deep experience. It’s a benefit to work with them early to understand roadblocks and address them.

What changed

The current environment in which a greater number of ADCs have been approved by FDA and are in the process of regulatory review shows that the industry has learned from the early failures of past ADCs. Improvements in ADC development have stemmed in part from ADC developers having optimized the selection of target antigens and expanding their toolboxes with new antibody constructs and payloads, confirms Michael Mulkerrin, PhD, vice-president, head of CMC, ADC Therapeutics.

“As a result, we’re able to develop and manufacture ADCs with the potential for increased potency, better efficacy profiles, and reduced side effects compared to earlier generations of ADCs,” Mulkerrin explains.

“We have seen ADCs evolve over the past 20 years as the field has learned better targeting mechanisms, understanding the delivery of the payload and the modulation of the drugability of the conjugate. From my perspective, we continue to challenge the historical limitations for bioconjugates and that is helping move the field to second and third generation successes,” adds McDermott.

McDermott also explains that there are now many new tools on both the process development and analytical front. These new tools are providing the ability to control the quality of the final materials that go into making an ADC. “All these advances are bearing fruit as we see the number of approvals increase,” she states.

In particular, linker technology has an influence on the process development for a new ADC. As McDermott points out, linker chemistry has been a rich area of modulation for ADCs. “The linker is a part of the construct that can be more easily modified to help with stability or delivery. Linkers can have solubilizers, additional handles for payload cleavage, and [linkers can] provide additional locations for multiple payloads for high DAR [drug/antibody ratio] constructs. From a manufacturing perspective, the linker can improve solubility during the conjugation process and improve the ability to clear the residual payload from the final product,” she explains.

Scaling up

In moving from the lab bench to commercial manufacturing, developers must look at what factors enable a robust scale up in ADC manufacture. Each ADC is unique and carries its own challenges, McDermott emphasizes. For each construct, it is important to understand the critical quality attributes early on, use proven scale-down models to develop the manufacturing process, and ensure close collaborations between development group and manufacturing teams, she states.

“Over the years we have developed templates for accelerating both the development and manufacturing of these complex molecules. This allows us to use prior knowledge to both accelerate early development as well as de-risk the unit operations needed for production,” says McDermott.

McDermott goes on to explain that it is important for the development team to design a quality-by-design process with a tight analytical control strategy and deep process understanding. She notes that, with a limited number of production runs before commercial supplies, having a historical database with trending data is critical to demonstrate control of the manufacturing process.

“ADCs are complex,” Mulkerrin iterates. “The development and manufacturing of ADCs requires significant planning and expertise.”

Mulkerrin emphasizes that toxin manufacturing can be particularly challenging and may involve several manufacturers to ensure the pathway is scalable and that the supply chain is able to provide all needed materials. In addition, deep knowledge of the supply chain is tantamount to success.

“Once the manufacturing pathway is established, the plan for future scale up should be created to ensure the necessary steps and process will fit in the manufacturing facility,” Mulkerrin states.

Addressing bottlenecks in manufacturing is another important task when it comes to ADCs. “We have spoken about templates being an important tool for de-bottlenecking bioconjugation development, and, as new conjugation chemistries are invented, additional templates will also be needed,” says McDermott. From her perspective, the industry also needs to continue to invest in single-use options, which offer a significant advantage in this high-potent space, both for the safety of the product and for the safety of colleagues.

Investments in ADC technology include the development of ADC-specific products that can be used specifically in the conjugation reactor. In some cases, advancing digital toolkits and investing in in-line and at-line process analytical technology has facilitated development. Some companies are also adding more capacity for both potent and novel-format conjugates, McDermott states.

Thus, with the lessons learned over the past decades, a once challenging category of therapeutic molecules are now reaping the benefits of deeper knowledge, understanding, and technological developments that have facilitated the growing approval of ADCs in the market.

About the author

Feliza Mirasol is the science editor for BioPharm International.