Overcoming the Complexities of Antibody-Drug Conjugate Development

One of my professors once said: “It is no problem to kill a cancer cell, the trick is to do that while keeping the person around it alive and well.” ADCs enable us to do just that –target the cancer cell directly with a higher local dose of the cytotoxic compound while significantly reducing the exposure to the healthy cells.

The critical part for this type of precision treatment comes down to identifying the right surface marker to use as the anchor. This needs to be prevalent only on the cancer cells in question. To date, ADCs have shown the most promise for treating blood cancers and solid tumors in the breast, cervix, bladder and lungs. 

It can be quite complicated to design the antibody (or other affinity molecule) drug conjugate complex in such a way that it retains its stability and, at the same time, is fully soluble. This is because they need to retain their stability while at the same time being fully soluble and transportable through the blood stream to reach their target. Antibodies by themselves are perfectly designed to do so, but when attaching a payload, the properties will change and this may have a negative impact on the biological properties required.

There are many to be considered, but the combination of good initial clinical results in models and a potentially simple and straightforward manufacturing process are always two good reasons for continuing the development.

With the growing number of ADC drug candidates in development, strategic prioritization is essential to efficiently allocate resources and accelerate the most promising therapies. Several factors come into play when deciding which candidates should advance, but two particularly important considerations are the strength of early clinical or preclinical results and the feasibility of manufacturing.

Strong initial data – whether from in vitro studies, animal models or early-phase clinical trials – can offer compelling evidence of efficacy, specificity and safety. Candidates that demonstrate clear tumor targeting, potent cytotoxic effects and a manageable safety profile tend to rise to the top. However, promising biological activity alone isn't enough.

Manufacturability plays an equally critical role. ADCs are complex hybrid molecules, and candidates with a more straightforward, scalable and cost-effective production process are more attractive for further development. This includes factors like the ease of conjugation, stability of the final construct and the ability to maintain consistent quality across batches. Simpler processes not only reduce production costs but also mitigate regulatory and safety risks – particularly important given the cytotoxic nature of the payloads.

Ultimately, prioritizing ADC candidates is about balancing scientific promise with practical feasibility. Those that combine biological effectiveness with a robust and efficient manufacturing pathway are best positioned for clinical and commercial success.

Since the ADC is highly cytotoxic, it is of utmost importance that the process itself is contained in such a way that it can ensure the safety of the operator. This starts once the payload is dissolved and introduced into the manufacturing process. Due to this, there is limited sampling during the process and a detailed process development is required to ensure a robust manufacturing process, with as few steps as possible.

All steps are important and many can be optimized. Think of the process from start to finish, where the start is the manufacturing of the monoclonal antibody intermediate and the finish is the vial with the filled ADC. The total cost will be that of the total manufacturing, so it’s best to focus on the initial steps where optimization is the easiest.

One of the most critical concerns is ensuring the safety of personnel throughout the manufacturing process, particularly given the cytotoxic nature of the payloads used. Once the payload is introduced – typically during the conjugation stage – strict containment measures must be in place to prevent operator exposure and environmental contamination.

This requirement for high containment limits in-process sampling and monitoring, making it more difficult to adjust or troubleshoot during production. As a result, ADC manufacturing demands meticulous process development upfront. Every step – from antibody production and payload synthesis to conjugation, purification and final formulation – must be precisely defined and tightly controlled to ensure consistency, safety and product quality.

Maintaining the stability and integrity of both the antibody and the conjugate throughout the process is also a major challenge. The conjugation step can alter the physicochemical properties of the antibody, potentially affecting solubility, aggregation and bioactivity. This necessitates careful selection of linker chemistry, conjugation methods and purification strategies to balance efficacy with manufacturability.

To address these challenges, manufacturers must adopt an integrated approach to process design, emphasizing containment, simplification and automation wherever possible. 

The more we know about surface markers specific to cancer cells, the more targets we will be able to use, which means more types of cancers will have the potential to be treated with an ADC. We’ll also be able to explore the use of a variety of affinity molecules, all with different properties and specificities that can open novel ways of pinpointing specific cells.