Simone Seechi, R&D Process Chemist at Olon and Matthieu Culié, Head of Development & GMP Manufacturing at GTP Bioways were interviewed by Citeline Clinical about the challenges in the development and manufacturing of ADCs.
What are ADCs and why is there so much excitement about them in the pharmaceutical industry, particularly in oncology and in combination therapies?
An ADC, or antibody-drug conjugate, is a complex molecule made up of three main components: an antibody, a cytotoxic agent (or payload), and a linker. ADCs are primarily used in oncology and are increasingly recognized as ideal biomolecules for cancer treatment.
The key to their effectiveness lies in the antibody, which is a product of the biotechnology industry. The antibody is designed to precisely target cancer cells by recognizing specific antigens present on their surface—antigens that are absent or rare on normal cells.
The second component is the cytotoxic agent, often called the payload. This highly potent chemical compound, derived from the field of chemistry, is released into the cancer cell after the antibody binds to it. Once inside, the payload destroys the cancer cell by various mechanisms, such as breaking down its internal structures. Typically, two to eight cytotoxic molecules are linked to each antibody. The selectivity provided by the antibody minimizes the payload’s harmful effects on healthy cells, making it possible to use extremely powerful agents that were previously too toxic for therapeutic use.
The third essential component is the linker. This small molecule connects the antibody to the cytotoxic agent and plays a critical role in maintaining the stability of the ADC and controlling when and where the payload is released. The linker’s design is vital to achieving a high therapeutic index, balancing effectiveness against cancer cells with minimal side effects.
ADCs can be thought of as a “Trojan horse,” sneaking into cancer cells to destroy them from within while leaving healthy cells unharmed. Their high selectivity and potency explain the growing enthusiasm for this class of molecules. For the first time, ADCs enable the safe use of extremely toxic agents that were once too dangerous to administer due to their effects on healthy cells. This breakthrough has generated significant hope for advancing cancer treatments, thanks to the specificity and efficacy of ADCs.
ADCs are highly complex products that are equally challenging to manufacture. In your view, what are the key technical challenges in ADC manufacturing?
ADCs are promising molecules in oncology, but unfortunately are not so easy to produce. This is mainly due to the dual properties of biotech and chemistry subparts. So the first technical challenge is to link the three parts of the ADC together, antibody, payload and linker, As I mentioned before. it is common to first link the linker to the payload, In the chemistry plant before The linking this dual to the antibody in the biotech unit. For the first linking, the synthesis of the payload-linker can be extremely challenging because long synthesis involving multiple types of reaction and technologies are required and difficult purification and isolation methods related to the limited stability of the final products are necessary. Moreover, all the operations need to be performed under highly containment, ensured by cutting edge technologies and highly specialized personnel. Thus, only very expert and innovative Players in the CDMO area can support this manufacturing of such products.
The operation of linking antibody and payload-linker suppose also to fine tune the process parameters. For example molecule concentration, pH or salt concentration, The process duration also. In order to have the desired amounts of cytotoxic molecule linked to the antibody molecule. But once the molecule is made, it’s not finished. Due to its high toxicity against healthy cells, it’s compulsory to eliminate the free linker-payload molecules that could remain in the media after the coupling reaction, and this is certainly the most difficult challenge in the biotech field. Because the free linker-payload, has a tendency to hang on the ADC freshly built. This is due to a balance of hydrophilic and hydrophobic interaction, on which we can play on to try to segregate the two molecules. ADCs can also be poorly stable molecules and then it’s becoming difficult to find conditions into which the molecule is stable Long enough to be administrated to patients. And to finish with, on a more general point of view, this payload cytotoxicity obliges the manufacturing area to be highly secured for operators for them not to be in contact with the molecules. We are then using isolators to manipulate the payload and operators who are integral suits and respirators.
Yes, indeed, some very complex challenges there. Simone, I would like to come to you now. I know that Olon uses design of experiments or DOE in the chemical and development side of ADC. So what’s the key advantage of DOE in this context? And how is Olon employing it?
First, let’s start by explaining what DOE (Design of Experiments) is. DOE is a statistical tool used to optimize reactions and processes by systematically varying multiple factors at once. It has become a cornerstone of the pharmaceutical industry’s quality-by-design (QbD) approach, which, while not mandatory, is strongly recommended by ICH guidelines.
The main advantage of using DOE in chemical development is its ability to evaluate several parameters—known as factors, such as temperature or material concentrations—simultaneously. This approach helps optimize product characteristics, known as responses, like yield, selectivity, or impurity levels.
When it comes to ADCs, process parameters such as molecule concentration, pH, salt concentration, and reaction times need to be fine-tuned. DOE allows these multiple parameters to be assessed simultaneously, providing a deeper understanding of the process while minimizing development time and reducing the number of experimental repetitions required.
Additionally, ADCs involve multiple purification steps that must also be optimized. For example, this could include chromatographic purification steps for the payload or the payload-linker system. Using a statistical tool like DOE strengthens the quality system by maximizing experimental responses and creating robust documentation, which is crucial for regulatory submissions. Ultimately, this translates into improved product quality for patients, which remains the primary goal.
To fully leverage the potential of DOE, Olon has established Centers of Excellence—teams of subject matter experts who support other workgroups. These teams work in synergy across the company’s various locations. One of these Centers of Excellence focuses specifically on DOE and quality-by-design approaches. They are often tasked with optimizing existing processes or developing strategies to industrialize entirely new ones. As such, they are well-equipped to take on ADC development projects.
Great. So how does Olon fit into the competitive landscape as a CDMO in ADCs and what would you say your particular USP is?
The first key point is Olon’s decades of expertise in containment technology. Our journey in this field began in the 1970s with pioneering containment systems for producing the first cytotoxic anti-cancer products. This early start established Olon as a global leader in the field. Today, we leverage our extensive experience in developing highly potent cytotoxic APIs, utilizing both synthetic and semi-synthetic capabilities.
While our history provides a solid foundation, Olon remains committed to continuous improvement. We maintain our leadership through ongoing investments in advanced technologies and skill development.
Our investment strategy goes beyond simply expanding capacity—it focuses on enhancing our capabilities in high containment across various production scales. Olon has advanced facilities for both chemical synthesis and fermentation under high containment, as well as deep expertise in high-containment purification steps, including chromatographic columns.
This commitment to containment extends to quality control. Fully compliant with CGMP regulations, our QC teams handle highly potent drugs using qualified glove boxes integrated within high-containment areas. We are also equipped with state-of-the-art chromatographic instruments, such as GC-MS and high-resolution mass spectrometry for nitrosamine detection, as well as specialized equipment for microbiological testing.
Very comprehensive. So you are a CDMO in the field, what you would say are the pros and cons of outsourcing all parts of ADC manufacturing to a single CDMO?
There are many advantages to working with a CDMO that specializes in ADCs and covers every aspect of the manufacturing process. Such a CDMO offers integrated expertise across the entire supply chain, which can lead to better process optimization, more effective troubleshooting, and greater innovation in drug development.
Another significant advantage is regulatory alignment. A single CDMO managing the entire ADC manufacturing process has a comprehensive understanding of the regulatory requirements at each step. This ensures compliance with GMP regulations, as well as FDA, EMA, and other international guidelines.
The end-to-end value chain offered by CDMOs is particularly attractive to customers who need an efficient and reliable partner with a strong track record. This is especially beneficial for companies with limited technical knowledge of ADCs or those that lack the capacity to coordinate multiple partners. By working with a single CDMO, project management is simplified, and supply chain coordination becomes more seamless with one point of contact.
On the other hand, a potential downside of end-to-end CDMO services could be gaps in expertise, such as limited technical knowledge in specific production steps. However, the new strategic partnership between Olon and GTP Bioways overcomes this challenge. This collaboration combines deep expertise and knowledge across all steps of the ADC value chain while maintaining a centralized management flow, offering a distinct advantage to customers.
Thank you. As we mentioned earlier, Olon acquired GTP Bioways quite recently and Matthieu was part of that. So Matthieu can ask you, what was the rationale behind the acquisition and how does GTP’s particular capabilities enhance Olon’s offer in this specific field?
The acquisition of GTP Bioways enables Olon to offer customers a comprehensive solution for ADC manufacturing, covering both clinical and commercial batches. Olon brings extensive expertise in developing and manufacturing payload-linker components, while GTP Bioways handles the biotechnology aspects of the process, including antibody and ADC production.
To be more specific, GTP Bioways’ antibody suite can produce batches up to several kilograms, and its ADC suite has already manufactured batches of ADCs up to 1 kilogram—sufficient for large-scale clinical trials. Additionally, another GTP Bioways site provides fill-and-finish services, completing the production process.
GTP Bioways also offers cell line generation for antibody development, enabling it to cover the entire spectrum of activities related to antibody development and manufacturing.
In summary, this acquisition positions us as one of the few players worldwide able to provide end-to-end services for ADC development and GMP manufacturing, supporting both clinical and commercial projects. Furthermore, our operations are entirely based in Western Europe, offering a strategic advantage to our customers.
Alright, thank you very much. So one final question. Technology is never stand still for very long. So what do you see as the key emerging challenges technical or otherwise in ADC’s and how will Olon address them?
In my opinion, off-target toxicity remains a significant challenge in ADC development. For instance, linkers can be either cleavable or non-cleavable, each with its own advantages and limitations.
Cleavable linkers are designed to release the payload inside the target cell through a lysis mechanism. However, they can sometimes be prematurely cleaved in the bloodstream or microenvironment due to the presence of cleaving agents. This can lead to increased adverse events but may also enhance efficacy by allowing the payload to affect cells with lower antigen expression.
Non-cleavable linkers, on the other hand, release the payload in a way that prevents it from diffusing across plasma membranes. This limits off-target toxicity but also reduces the impact on neighboring tumor cells. As a result, choosing the right linker is a complex but critical decision that offers opportunities for customization and optimization.
Another key challenge is the evolving regulatory landscape for ADCs. These therapies combine biological and small molecules, requiring extensive data on pharmacokinetics, toxicity, and efficacy. The complexity of ADCs demands highly specialized testing and validation processes.
With its extensive experience and proven track record across all stages of the API lifecycle, Olon is well-equipped to navigate these challenges. From early-stage development to advanced commercial phases, Olon provides the necessary expertise and comprehensive documentation to meet regulatory requirements, making it the ideal partner for ADC projects.
Thank you. We’ve run out of time, so thank you both Simone and Matthieu for that taking the time to have this conversation today. I’d also like to thank the sponsor of this podcast, Olon, for making this great discussion possible. Thank you and goodbye.
