The promise and challenges of Antibody-Drug Conjugates: CPHI North America insights – part 1

In this blog, we’re taking a closer look at Antibody-Drug Conjugate (ADC) development. We’ll be drawing insights from a fascinating presentation by Dr. Kishore Hotha, the Global Vice President of AR&D Operations at Veranova, given at CPHI North America. 

Dr. Hotha’s talk, ‘Navigating Four Pillars of Safety, Development, Supply Chain and Manufacturing Excellence in the Antibody-Drug Conjugates (ADCs) space’, offered a wealth of valuable perspectives on the intricacies and possibilities of this groundbreaking therapeutic approach. 

Let’s dive in, explore the key takeaways from this insightful presentation, and shed some light on the future of ADC development in part one of our two-part series.

ADCs on the rise

ADCs are a rapidly growing pharmaceutical modality that offer improved patient outcomes, including reduced side effects and higher drug tolerability. In particular, ADCs have shown great potential for cancer treatment due to their ability to selectively deliver potent cytotoxic drugs directly to cancer cells while minimizing off-target toxicity to healthy cells. This targeted delivery approach results in an improved therapeutic window compared to conventional chemotherapy, allowing for better efficacy and reduced side effects. ADCs offer additional advantages, such as the potential to overcome certain drug resistance mechanisms mediated by efflux pumps, as the antibody-drug complex is internalized into the cancer cell. 

The clinical success of several FDA-approved ADCs, including Adcetris (brentuximab vedotin) and Kadcyla (trastuzumab emtansine), has demonstrated the therapeutic potential of this modality, and fueled further research and development efforts in the field. The potential of ADCs has sparked significant M&A activity. Pfizer’s $43 billion acquisition of Seagen in 2023, a leader with approved ADCs like Adcetris and Padcev (enfortumab vedotin), solidified their dominance in the space. Similarly, AbbVie’s $10.1 billion acquisition of ImmunoGen in 2022 secured them the innovative ADC Elahere (mirvetuximab soravtansine), bolstering their oncology portfolio with a promising targeted therapy.

The growth of ADCs as a pharmaceutical modality is driven by ongoing technological advancements in antibody engineering, linker chemistry, and the identification of potent cytotoxic payloads. These advancements have enabled the development of more effective and stable ADCs, further enhancing their clinical potential. The combination of targeted delivery, improved therapeutic index, ability to overcome resistance mechanisms, clinical validation, and continuous technological progress has positioned ADCs as a rapidly growing and promising modality for cancer therapy.

Challenges of ADC development and manufacturing

As nicely described by Dr. Kishore Hotha at CPHI NA, the manufacturing of ADCs faces several challenges. These complexities are due to the intricate requisites of the production process, stringent safety protocols, and the inherent variability in ADC products. 

A critical challenge in ADC development is the design and optimization of ADC linkers. Linkers play a pivotal role in ADC efficacy by connecting the antibody to the payload drug. They must be carefully designed to ensure stability during preparation, storage, and systemic circulation. Tailoring linkers to bear different release mechanisms involves modifying payload drugs and formulating the drug-linker complex, demanding extensive chemistry expertise and potent manufacturing experience.

In addition to technical demands, the production of ADC linkers poses various operational and analytical difficulties. The intricate nature of these linkers necessitates the use of complex analytical, biochemical, and biophysical methods for their characterization. From a manufacturing standpoint, a controlled environment with cGMP aseptic conditions and reliable containment strategies are essential to safeguard the well-being of personnel and prevent the release of potentially toxic drug compounds into the surrounding area.

Safety was indeed pointed out by Dr. Hotha as one of the biggest concerns. From implementing industrial hygiene practices, storage protocols and establishing exposure limits, to ventilation and personal protective equipment, a careful safety assessment is needed for the safe handling of ADCs in pharmaceutical facilities.

On the other hand, complex supply chains often involve multiple manufacturing facilities to ensure alignment with intricate production requirements. The upstream supply chain for ADCs involves sourcing and procuring critical raw materials, including monoclonal antibodies, cytotoxic payloads, and linkers. These materials often originate from different parts of the world, making the supply chain susceptible to various risks, including geopolitical tensions that can disrupt the flow of raw materials and increase costs and natural disasters that can disrupt transportation routes and production facilities. Furthermore, variations in regulatory requirements across countries can lead to delays, and compliance challenges and economic instability can impact the cost and availability of materials.

These complexities can cause delays in production, increase costs, and potentially compromise the quality of ADCs. Therefore, it is essential for pharmaceutical manufacturers to proactively manage such risks and ensure supply chain resilience. The ultimate goal is to establish a scalable supply chain, but while managing small quantities initially may seem straightforward, the true complexity emerges during scalability for production and distribution.

Collaborating with multiple partners for those operating in this space also comes with challenges. With ADCs involving various stakeholders, including biotech companies, pharmaceutical companies, and contract development and manufacturing organizations (CDMOs), it becomes imperative to establish effective communication channels, align goals, and meet tight timelines and budgetary requirements. Understanding demand, whether for clinical trials or commercial sales, is crucial, and accurate data is needed to guide realistic production planning decisions, including batch size, facility selection, and staffing.The selection of an appropriate manufacturing partner with aligned communication, decision-making, and quality standards is paramount for a successful manufacturing relationship.

Part 2 of this conversation