It is an exciting time to be an Antibody-drug conjugate (ADC) developer, driven by advances in chemistry, including novel linker-payload combinations, site-specific conjugation, and improved control of the drug-to-antibody ratio (DAR). Given the potential to target a wide range of cancers and previously untreatable indications, developers and manufacturing partners are working to mitigate the risks and challenges of ADC development.
In a recent webinar on the increased manufacturing complexity of bioconjugates, experts from Abzena and Frost & Sullivan highlighted key features to identify in a bioconjugate CDMO, which were primarily integrated capabilities across the drug life cycle, rigorous analytical offerings, and in-depth scientific knowledge and experience. The panelists also provided the following insight into audience questions on how CDMO selection criteria is evolving.
Q: What are the most important trends shaping the ADC and bioconjugate market today?
Dr. Campbell Bunce, Chief Scientific Officer, Abzena: At Abzena, we are lucky to work with so many exciting next-generation molecules. We’re seeing three trending areas. One is technology developments, particularly conjugation technologies that support site-directed conjugation, allowing better control the DAR, improved stability, and increased yield. Abzena has their own proprietary conjugation platform called ThioBridge®, which alongside other platforms opens up the potential for different cargoes to reach distinct disease indications. We have learned a lot from classical ADCs that has allowed us to understand where the limitations are and areas of improvement leading to development of new conjugation and linker technologies supporting more options for development of optimized ADCs.
The second area of growth is with Antibody-oligonucleotide conjugates [AOCs], which open the treatment of new disease indications such as muscular dystrophies, cardiomyopathies, neurodegenerative disorders. The potential is massive.
AI is a third area. It’s a slow burn in terms of using AI to optimally design ADCs or optimize processes, but it is starting to build momentum. AI is being increasingly used to discover new targets that we can design ADCs and novel bioconjugates to that provide better drugs for difficult to treat indications.
Unmesh Lal, Vice President, Healthcare & Life Sciences, Frost & Sullivan: One major trend amid geopolitical pressure is the regionalization of supply chains. We are seeing the growth of strategic onshoring and end-to-end capability provision. Analytical sophistication is both a key differentiator and an unmet need in the industry for biotech companies.
Q: How are sponsors rethinking CDMO selection criteria? Which capabilities have become essential versus merely desirable?
Lal: CDMO selection framework varies by modality — biologics versus small molecules — but it has shifted over the past three years. The conversation used to begin with capacity: Do you have available conjugation slots? What is your containment level? Can you hit our timelines? Those remain critical qualifiers, but they are no longer sufficient deciding factors. Sponsors have learned, sometimes expensively, that capacity without deep process knowledge and analytical capability can lead to program liabilities. Essential capabilities include GMP-compliant conjugation infrastructure with OEB4 and OEB5 containment, and end-to-end integration across antibody production, conjugation, analytics, and drug product.
Many CDMOs claim to have end-to-end capabilities, but when we start benchmarking them across these capabilities, we see a different story. Regulatory track records are also critical. In addition to that, you want to see competency in tech transfer. For some of the newer modalities, proprietary conjugation platforms, in-house HPAPI, linker payload synthesis, and geographical footprints are clear differentiators.
Bunce: The buying behaviors of ADC developers are evolving. We work with a wide range of customers, from spinout startups to established biotechs to big pharma. Increasingly, ADC developers are moving toward having systematic capabilities, from cell line development to making the antibody, Fab, or recombinant protein, alongside expertise around linker payload design and optimal route of synthesis. It is also important to have flexibility around platform conjugation methods to accommodate new linker-payload molecules. This enables us to progress from gene to IND faster and with less risk.
Q: How is the business model for CDMOs changing as biotechs demand earlier derisking, faster development timelines, and more accountability across the life cycle?
Lal: When we speak to biotechs versus big pharma, we see subtle differences in terms of their optimal business model. The traditional model is very transactional: a sponsor pays for defined deliverables such as GMP batches and an analytical report. This is being disrupted by two forces: biotech sponsors need more support when it comes to execution, and CDMOs face competitive pressure to differentiate themselves beyond pricing. We are seeing, particularly for bioconjugates, a shift from transactional dynamics to core development and life cycle accountability partnerships. There is also an increased number of milestone-based business models and outcome-oriented commercial structures. Other strategies include dedicated program teams and capacity reservations.
Bunce: As a heads-down, hyper-focused contract organization, one thing we sometimes overlook is asking clients about their goals. This could be getting to clinic quickly to establish early clinical data to leverage the value of their technology to be acquired or building a pipeline around a platform antibody or Fab and determining the optimal manufacturing cadence towards phase III and commercial requirements. At Abzena, we’re paying closer attention to our customers’ goals, and how we can support them.
Customers are looking for agility, flexibility, and data-driven decision-making. If data in the early stages of development reflects issues down the road, we need to be nimble enough to pivot. Our technical excellence oversight team, made up of seasoned drug developers and biotech experts, works with our key integrated customer programs to better understand their strategy and then collaborates internally with project management and the technical teams to deliver that strategy.
Lal: The Abzena business model resonates with sponsors. Being able to grow with the client, particularly biotech companies, is important given the challenges and pressures they face. This is what differentiates specialist CDMOs from some of the tier one vendors.
Q: What is the proper DAR for AOCs?
Bunce: We must account for the optimal potency and stability of the AOCs and consider that we are combining two large molecules of different charges together. Consequently, to manage the stability of the AOC the DAR is typically low i.e. 1. .
We have, however, seen different conjugation methods to manage DAR2. You can utilize engineered cysteines to allow site directed conjugation to specific locations of the antibody to manage stability and DAR. ThioBridge® works particularly well with oligonucleotides because it re-bridges across the Fab’s disulfide bonds to create a stable, scalable, high-yield AOC. There is a lot of development in next-gen platforms for conjugation and linker architectures that allow us to stabilize more difficult cargos.
Q: When benchmarking CDMOs in the ADC market, what differentiates leading players beyond scale or installed capacity?
Lal: In the research we conducted, we started with a list of 50 ADC CDMOs and applied growth and innovation metrics to benchmark these vendors and get feedback from sponsors. We identified 16 leading ADC CDMOs globally. The criteria we found most critical were proven commercial-scale execution, multi-year regulatory track record, end-to-end capability, and commitment from a CapEx perspective.
It was also important to consider their proprietary technology platforms, analytical depth, and assay development solutions. End-to-end integration from both a biology and chemistry perspective and CMC expertise are critical. Finally, the earlier that sponsors and vendors engage, the more likely that they will have a long-term partnership with customer satisfaction.
Bunce: Another quality that is particularly popular is a holistic approach and broad capability offering. Because ADCs are still relatively new to regulators, sponsors like to see a proactive approach to bringing the Regulators along with these new technologies. We have a dedicated regulatory expert on our team and find that regulators like to see orthogonal data to help understand and inform the properties of ADC’s.
Q: Where do you see the most compelling growth opportunities for bioconjugate CDMOs over the next three to five years?
Bunce: Developers are getting bolder in molecular design. For example, bispecifics that bind to two different targets with dual payloads. We need optimal conjugation platforms that work well together to make this type of ADC a reality. This is possible if we are clear-eyed about the upfront design and developability aspects, rather than shortcutting development to get into the clinic as quickly as possible with a product that cannot be scaled to satisfy the patient population. New designs open the possibility to treat different disease indications that have unmet need, which is extremely exciting.
Lal: With next-gen modalities, antibody-siRNA conjugates [ARCs] are another interesting area. We are seeing the value proposition of antibody-to-vial and which CDMOs are building platforms and capabilities to capture that downstream value. The industry has also been exploring the adoption of digital twins in manufacturing.
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About The Authors
Campbell Bunce, PhD – CSO at Abzena
Campbell has over 25 years of experience working in the biotech and diagnostics sectors. Before joining Abzena in 2015, he held multiple positions of increasing responsibility in Biotech including Head of Cellular Immunology at Cantab Pharmaceuticals, Director of Programs at Piramed Pharma, and R&D Director at Immune Targeting systems. Throughout his career, he has applied innovative solutions for the design, manufacture, and clinical evaluation of novel products, including vaccines, biologics, and small molecules, in multiple therapeutic areas. These include inflammation, cancer, infectious disease, and addiction. Campbell has a Ph.D. in Immunology from the University of Manchester, UK, an Executive MBA from Judge Business School, Cambridge University, UK and has published a number of papers on cell-mediated immunity, immunotherapy and vaccines.
Unmesh Lal, PhD – VP of Healthcare & Life Sciences at Frost & Sullivan
Unmesh Lal has 20+ years of healthcare industry with expertise, primarily comprising of strategy advisory with global life sciences companies. His expertise lies in tracking game-changing companies, innovative business models and disruptive technologies while serving as a growth coach to clients in their precision health journey. He has authored thought leadership and presented at leading industry events like J.P.Morgan, BIO-Asia, CPHI World, Bio-IT, Medica Health IT, Medtec, Precision Medicine Exhibition & Summit, Basel Life, to name a few. His in-depth understanding of the precision health ecosystem enables him to guide companies in identifying growth opportunities across precision screening and diagnosis, personalized therapeutics, surveillance & monitoring, and discovery & development solutions/service. He holds a master’s degree in biomedical engineering from the University of Michigan – Ann Arbor.
