Perks and Pitfalls of Antibody Drug Conjugates: Lessons Learned with Charlie Johnson
ADCs have suffered a few setbacks over the years, but interest in their therapeutic potential – particularly against cancer – remains high.
Charlie Johnson has kept his eye on the antibody drug conjugate (ADC) field since its early days and was involved in developing the process for one of the first ADCs to hit the market, as well as helping to establish Avecia’s ADC manufacturing operations. Today, he is CEO of ADC Bio. Here, he talks about the ups and downs of the ADC market, and shares the lessons he has learned as ADC Bio gears up to jump into GMP manufacturing.
New classes of therapeutics take time to find their feet
I’ve always been fascinated by ADCs. In many ways, ADCs combine the best of both worlds: the potency of cytotoxic agents with the specificity of antibodies. The targeting ability has been of particular interest to drug developers working on cancer therapeutics. But although the industry has been talking about ADCs for years, approvals have been thin on the ground. ADCs have shown promising data in terms of having an effect on tumor cells, but there have also been unintended side effects as the target antigen on the tumor may also be present in healthy tissue. The translational science of ADCs has been very challenging, but a lot of it comes down to choosing the right targets. Right now, there is a great deal of attention being paid to more exquisite targeting; for example, using bispecific ADCs.
It is normal for new areas of science and drug development to suffer some setbacks, but there is now a renaissance in the ADC area, thanks to growing understanding and experience with ADCs. Two new products were approved in 2017 and there are over 80 ADCs in clinical development, as well as thousands of patents filed. And new research is being published constantly as the community strives to improve safety and efficacy (for just some example papers published in 2019, see the sidebar). Oncology remains the top area for ADC drug development, but other areas are also being explored, such as inflammatory diseases and even bacterial infections.
Aggregation is a major manufacturing challenge
As well as innovation in terms of ADC development, improvements in manufacturing have focused on speeding up, simplifying and significantly lowering the production costs. My work with ADCs began back in 2005. I was working in Scotland at a clinical manufacturing facility for small molecules (mainly cytotoxics) and we received a visit from a small company that I had never heard of before: Seattle Genetics. They were developing what would later become Adcetris and we were involved in developing the process for them.
After I left the company, I kept my finger on the pulse with ADCs. The field certainly had its challenges, but I was not only fascinated by the way they worked and their therapeutic potential but also by the interest shown by companies. Around 2009, I had a conversation with an ex-colleague who had come across a piece of intriguing chemistry that he thought could help us towards a solid phase approach to ADC manufacture.
Currently available ADCs get around the aggregation issue with finely tuned processing, but many ADCs in development now use pyrrolobenzodiazepines or duocarmycin-based payloads, which are very potent but also dramatically increase the drug’s propensity to aggregate during conjugation, which is expensive and time consuming to deal with. By using proprietary beads to immobilize the antibodies, payloads can be conjugated in situ, which physically prevents aggregation at the source. It also means you get a very high-purity ADC.
Pharma companies want you to do as much work for them as possible
Inspired by the technology, we worked to optimize it with the University of Sheffield. ADC Bio was formed in 2010. Our initial aim was to license the technology out to pharma companies. Though there was a lot of interest, there was also a common theme: companies wanted us to actually do the work for them.
So that’s the direction we went in. We only focus on ADCs. Our proprietary technology is called Lock-Release, and we’ve done the work to ensure it’s scalable and meets GMP requirements. But we also do mainstream ADC development too, including small-scale work that has gone into trials in non-human primates. We were a small company at first – we had nine people in 2014 but things changed quickly. We’ve expanded a lot and by 2015, we were turning over £1.5 million. We signed many agreements and even won an award with the British Private Equity and Venture Capital Association!
But still customers wanted more. Many clients were encouraging us to get further involved in their development programs; they wanted us to move into GMP manufacture and clinical trials. It was a big move. ADCs are still relatively new compared with established monoclonal antibodies, but after we discussed the expansion we were confident it would work. Between us we had a lot of experience in ADCs, so the question became: why not take the plunge?! The hardest part of making an ADC is the design and development, but GMP is where pharma customers see the most value as it’s directly connected to the patient. In fact, GMP is relatively simple compared with other aspects of ADC development. Once a recipe has been defined, it’s simply a case of following the recipe at scale – providing your process development is solid.
The decision was made – and we went to our investors and told them we wanted to build a clinical manufacturing facility. It took time, but we got the funding. We acquired a 6500 m2 facility in Deeside, UK, in 2017. Construction has finished and we’re awaiting inspections as we speak; we have been liaising with the MHRA throughout the design and construction process We are now part way through the accreditation to obtaining the necessary license to produce ADCs for human trials.
Build flexibility into your facility design
Experts will tell you that the design and build of a new facility takes time – and they are absolutely correct! Flexibility is extremely important. While we were in the process of building our Deeside facility, there was a big shift in the ADC marketplace. There are four elements of manufacturing an ADC: you need an antibody, a payload, the conjugation, and then fill and finish. Not all pharma companies want to do this in house so outsourcing is a common option and, in some cases, each element will be manufactured at a different site. Today, however, companies tend to want their partner to tackle multiple aspects – perhaps make the antibody and do the conjugation with the payload, or do the conjugation and the fill and finish. The reason? Time. It saves the pharma company a lot of time in development. They can also save costs because they need fewer people and aren’t dealing with complex work.
Having more than one part of your supply chain with one vendor also contractually makes things a lot simpler and gives you more flexibility to overlap the next stage of manufacture with completion of testing in the preceding stage. If you are transferring to another site then you must ensure the product is always to specification. But if you have formulation under the same roof, the client can ask you to try different approaches with the idea of compressing time or investigating ways to make processes more efficient.
As well as performing ADC manufacturing and conjugation, we are also moving into fill and finish. Fortunately for us, we prioritized flexibility when looking for a site so we have the ability to build in this new expertise. You always need to think ahead when building a facility. If anyone were to visit our facility now, they’d notice some corridors that seem to go nowhere. And they do go nowhere – for now! But in the future, they will lead to new areas of capability. I would say that flexibility is especially important for ADCs because product demand his so variable. Some ADCs have a global demand of only 5 kg while others may be in the region of 300 kg or more. It’s important to have a facility that can cope with those extremes, but be able to scale if demand changes in the future.
Location Matters
One of the conditions of receiving investment was our presence in Wales, UK. But this also gave me a whole new appreciation for how difficult it can be to find an appropriate site for a facility – especially, as we didn’t want to invest money on infrastructure unnecessarily. It was easy to find great sites, but they all required millions of pounds to install the electrical supply we needed. At almost the eleventh hour, the Deeside site became available. It had previously been used by Catalent for warehousing and distribution. It had space. It had power. And it had more space to expand into in the future.
Shortly after Catalent exited, it was raided by thieves for copper wiring. But that’s another story… In short, never underestimate the challenges of finding a site and getting it up and running!
A blank sheet of paper can be a joy
We’ve been hiring a lot of staff recently – and we’ve been successful in attracting very experienced people. Some of them have chosen to leave big pharma and come work for us because we offer a blank piece of paper – the ability to do something from scratch and run your own process. Big pharma has been (and can be) very successful but there are some downsides; big companies tend to be systemized and procedural, so change does not come easy. At a new, smaller company you can employ what you have learned in the past; you can cherry pick ideas and build your own process – it’s all been very exciting. It’s also been stressful, of course! Often in the contract manufacturing market, everything comes down to price, which is unfortunate. However, we decided to focus on building up our technical capability before committing to a facility, which allowed us to showcase the skills and knowledge we have to offer. It is this that sets us apart in this segment of pharma outsourcing – we are recognised by clients as the experts in ADC development. Ultimately, the experience we have gathered is the invaluable asset that helps us navigate this complex field for our customers – we help them advance faster and overcome the many pitfalls that might have prevented a highly promising therapy making it to patients.
Recommended Reading
- M Abdollahpour-Alitappeh et al., “Antibody–drug conjugates (ADCs) for cancer therapy: Strategies, challenges, and successes,” Journal of Cellular Physiology, 5 (2019).
- L Bourillon et al., “An auristatin‐based antibody‐drug conjugate targeting HER3 enhances the radiation response in pancreatic cancer,” International Journal of Cancer (2019).
- C Duerr, W Friess, “Antibody-drug conjugates- stability and formulation,” European Journal of Pharmaceutics and Biopharmaceutics,” 139, 168-176 (2019).
- JB White et al., “Design and characterization of homogenous antibody-drug conjugates with a drug-to-antibody ratio of one prepared using an engineered antibody and a dual-maleimide pyrrolobenzodiazepine dimer,” mAbs, 3 (2019).
- M Lin Yap, “Activated platelets in the tumor microenvironment for targeting of antibody-drug conjugates to tumors and metastases,” Theranostics, 4, 1154-1169 (2019).
- M Jose Costa et al., “Optimal design, anti-tumour efficacy and tolerability of anti-CXCR4 antibody drug conjugates,” Scientific Reports, 9 (2019).
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