Q&A: Small molecule and biological aspects of ADC manufacturing
Lonza recently announced the completion of the expansion of its Highly Potent API (HPAPI) multipurpose suite in Visp (CH). The expansion adds development and manufacturing capacity for Antibody-drug conjugates (ADC) payloads, supporting the entire development and manufacturing pipeline from feasibility studies to commercial supply.
EPM chats with Lonza's Giovanna Libralon, Small Molecules, and Iwan Bertholjotti, Bioconjugates, who share insights on payload-linker manufacturing and the global market trends for ADC-based therapies, along with the production of antibodies that help increase the precision of ADCs.
Experts:
Giovanna Libralon, senior director, Commercial Development – Small Molecules
Iwan Bertholjotti, senior director, Commercial Development and Strategic Marketing – Bioconjugates
Q: From a high-level, can you provide an overview of ADCs and how they provide targeted treatment?
Libralon: Antibody-drug conjugates (ADCs) are quickly emerging modality for precision medicine that combines the selectivity of antibodies and the high potency of small molecule payload-linkers. In laymen's terms, ADCs consist of three components: the targeting antibody, the linker molecule, and the highly potent payload. Manufacturing each of these components brings several complex challenges.
Bertholjotti: In oncology, its targeted nature is enabled by the antibody that delivers the payload to cancer cells expressing the target antigen, which allows deliver its therapeutic effect with fewer side effects than other traditional therapy options.
Q: In simpler terms, how are ADCs manufactured? What are the biggest challenges manufacturers face during development?
Libralon: Manufacturing each of these components brings several complex challenges. The linker molecule and highly potent payloads are almost always small molecules. Given its highly potent nature, manufacturing these compounds requires very specific containment and handling procedures to ensure the safety of the operators and the analysts. Our new HPAPI suite in Visp (CH) allows us to manufacture these HPAPI payloads at scale with high flexibility and increase our capacity to respond to the growing global needs for ADCs.
Bertholjotti: In addition to the small molecule HPAPI related challenges, the antibody and the Bioconjugation also require complex manufacturing capabilities. The production involves very complex biological processes that require strategic supply chain management and deep theoretical and working knowledge to handle Biologics. Building and investing in facilities specialised in the manufacturing process can be resource-intensive; thus, choosing the right development partner is critical to the success of the ADC therapy. With this new fully integrated offering in Visp, we can simplify the supply chain under one roof: from the production of an antibody to the chemical synthesis of complex payload-linkers and bioconjugation.
Q: What are some recent advancements in the development of ADCs?
Libralon: We’re currently seeing a rise in the ADC pipeline with a strong diversification of payloads with new mechanisms of action in pre-clinical phase. The selectivity of ADCs allows the development and application of payloads that cannot be administered systemically due to their high toxicity. This combination allows for several potential applications, and we’re optimistic about its role in the future of precision therapy.
Bertholjotti: On the biologics front, the commercial manufacture of monoclonal antibodies has become more streamlined as advancements in technology and regulatory understanding evolve. Different conjugation technologies and payloads passed the important cliff to get approved representing a proof of concept. In addition, novel conjugation technologies, for example site specific conjugations, improve the definition of drugs and will offer new potential in the future. Different payloads will further diversify the application of Bioconjugates/ADCs. Lonza is involved in very different Modalities including Polymer, Peptide, Oligonucleotide, Chelators for Radiolabelling and connection of different microbial derived Serotypes for Vaccines beside the meanwhile classical high potent payloads. Mature CDMOs are fully equipped to support customers from pre-clinical to commercial stage with Development and Manufacturing Service ideally under one roof as Lonza can provide.
Q: What are the market trends that drive the demand for ADCs?
Libralon: There is also an increasing number of ADC approvals in the last couple of years. After the first ADC got approved in 2000, it took until 2011 for the next one to get clearance with further approvals in 2013 and 2017.
However, this has quickly accelerated in the last four years. From 2018 to 2021, seven ADCs were approved by the FDA, suggesting a rapid acceleration in both understanding and use cases. This is reflected in the high activity in the development pipeline, on top of the dozen anticancer ADCs already in the market.
Bertholjotti: The demand for ADCs is driven by the need for improved anticancer therapeutics with fewer side effects. Many cancer therapies on the market cause damage to healthy tissue outside of the therapeutic area. This off-target activity results in adverse side effects for the patient, making their life even more difficult atop of fighting this already-challenging condition. The precise nature of the ADC decreases these side effects, which is exactly what drives the demand for anticancer ADCs.
Q: How does the expansion of the Visp site address current demand for ADCs?
Libralon: The expansion allows us to increase capacity and add larger equipment for commercial manufacturing, supporting our partners’ ADCs to meet the growing global demand for these therapies.
The new HPAPI suite enables handling compounds with an occupational exposure limitdown to 1 ng/m3, with various containment solutions and a flexible setup for executing different types of operations. Equipment on-site includes reactor sizes from 1 L to 50 L with a temperature range of -80°C to +150°C, isolation and drying equipment, lyophilisation and chromatography for the manufacture of payload-linkers.
Q: In the next 5-10 years, what does the future look like for ADCs?
Libralon: There are many new ADCs under development in the preclinical stage. I’m optimistic about how these therapeutic areas will diversify outside of oncology in the next couple of years, as several ADCs in the pipeline already address musculoskeletal conditions and autoimmune diseases.
Bertholjotti: The future has an exciting potential for a continuous flow of new ADCs into the clinic and market. As there are a lot of unmet needs for difficult to treat diseases such as cancer, there is a healthy competition between different technologies and modalities. Whatever concept improves the lives of patients suffering from these conditions will be a success, and I expect ADCs will play a relevant role in that.
The innovators bringing these drug products to the clinic are no longer just big pharma companies – although they do still dominate the current approval list for ADCs. Many ADCs are now being developed by small biotech companies. All the way from preclinical evaluation through the clinic to commercial launch, these businesses are almost entirely reliant on outsourcing partners to produce material.