Navigating the Challenges and Complexities of ADC Development

In the intricate and highly specialized arena of targeted oncology therapies, ADCs hold promise for safer and more effective treatment options. Developed as “biological missiles,” ADCs are composed of a monoclonal antibody covalently attached to a cytotoxic drug, aiming for high specificity in targeting and potent effects in eliminating cancer cells. 

The maturation of ADC technologies has broadened their scope of use, with a growing number of ADCs being approved or in late-phase clinical trials for various tumor types. These developments are driven by the increasingly diversified antigen targets and bioactive payloads, as well as enhancements in intratumor distribution and activation, which can potentially improve the anticancer activity for difficult-to-treat tumor types (1).

However, the development of effective and safe ADCs is complex and requires a multidisciplinary approach (2). One of the key terms that guide the ADC development process is developability. This term encapsulates a range of considerations that go into finding the best lead molecule for targeting a specific disease. It’s not just about creating ADCs; it’s about rigorously assessing them from various angles, including functionality, specificity, safety, and stability.

The right candidates
 

When discussing the functionality of ADCs, we must not merely consider their ability to target and destroy cells; we need an all-encompassing evaluation using a range of methodologies. High-throughput screening quickly distinguishes promising ADC candidates by assessing important parameters, such as binding affinity and payload release, while cytotoxicity assays provide insights into cell viability post-ADC exposure, revealing both lethal and sub-lethal effects.

Advanced imaging techniques, such as confocal microscopy, offer real-time visual insights into an ADC’s interactions with cells, highlighting uptake and internal trafficking processes. These tools, combined with 3D viability assays on spheroid cultures as solid tumor models and real-time viability assays to monitor the kinetics of cell killing, offer a comprehensive perspective on an ADC’s functionality. By integrating data from these methods, researchers can not only confirm an ADC's efficacy, but also thoroughly grasp under what conditions it performs optimally.

Another crucial aspect of ADC development is specificity. Because of the potent cytotoxic agents they carry, ADCs need to be highly specific to their target to minimize off-target toxicity (3). Flow cytometry and tissue profiling through immunohistochemistry (IHC) can be used to evaluate this specificity. IHC allows for the localization and visualization of the ADC within tissue samples, thus confirming that the ADC is binding exclusively to its intended target. Combining both flow cytometry and IHC helps mitigate risks associated with off-target effects that could compromise safety.

Of course, safety is paramount in the development of any therapeutic agent. With ADCs, developers should assess interactions with Fc gamma receptors, and conduct off-target profiling. One specific area where safety comes into play is the “bystander effect” – a phenomenon that relates to how an ADC impacts not just the target cells, but the surrounding non-target cells, either enhancing or mitigating its overall therapeutic effect depending on the disease context.

Keep it stable
 

Stability and formulation development are also crucial for success. The ADC must remain stable during its journey from manufacturing to delivery within the patient; it is vital that the ADC does not release its payload prematurely, causing systemic toxicity. In this regard, lyophilization has emerged as a popular technique to improve the stability of ADCs, especially during shipment (4). 

One common method of evaluating stability is “ex vivo serum stability” where the ADC is incubated with either human or animal serum for various time points. After incubation, the sample undergoes analytical processes to assess whether the ADC retains its original composition or has started shedding its payload. This type of ex vivo serum test provides critical insights into the ADC’s behavior in a biological environment.

The ADC can be reconstituted in different buffers, subjected to varied temperatures, and left for specific durations to evaluate its stability. In this manner, researchers can understand how different formulations affect the ADC and make informed choices for long-term storage. When a candidate ADC reaches a mature development stage, it moves into larger-scale manufacturing and, eventually, clinical studies. Ensuring that the product remains stable during these phases is paramount, as any instability can derail both the manufacturing process and clinical trials.

A holistic approach
 

To conclude, the development of ADCs is a complex but incredibly promising field that requires a multi-layered approach for success. A one-size-fits-all approach is not appropriate. The complex interplay between an ADC’s antibody, linker, and drug payload means that each component requires meticulous consideration. The biological precision in targeting the correct antigen or receptor is paramount – and so is stability, where considerations regarding linker chemistry and delivery methods may necessitate tailored solutions. 

A holistic approach for ADC design, development, and manufacturing should include experts from various research areas, including  chemistry, analytics, bioassay, and process development from the very beginning. With this approach, you can maximize the likelihood of finding the most promising candidate and design. However, don’t be afraid to lean on external experts when needed. Collaboration can be an accelerator for success in the complex journey of drug development. Partnering with another company that excels in a desired methodology, such as state-of-the-art analytics or advanced imaging techniques, can streamline the development process, ensuring that the ADC is rigorously tested under varied conditions.

Using a strategic blend of efficacy, safety, and stability assessments will help ensure the eventual success of your ADC. With each step meticulously planned and executed, the chances of developing a successful ADC increase, bringing us one step closer to more effective and safer cancer treatments.