14 November 2017, Wales: ADC Biotechnology (ADC Bio)‘s leading experts warn that best in class ADCs are being overlooked due to critical aggregation control problems. CDMOs are unable to develop products which are capable of working successfully in clinical testing or which are economically viable. The warning comes as more and more full service CDMOs are investing in conjugation and ADC facilities.

 “There is a major challenge in the ADC pipeline that conventional manufacturers have not addressed and which pharma companies are obliged to work around. The ultimate problem is that you have a candidate that may look promising but in practice it can’t be commercialised – unless aggregation control systems are put in place” commented Charlie Johnson, Chief Executive Officer at ADC Bio, the specialist ADC contract services company. He added: “We are seeing a great deal of excitement from pharma companies seeking to invest in ADC therapeutics. But applying conventional manufacturing techniques will see the drugs fail or endure very long periods in development. From the vendor side, there is considerable investment across the industry in facilities – but that alone will not give you the capabilities to commercialise optimal ADC therapeutics and that is ultimately a failure to patients desperately in need of new life-saving therapies.”

This is especially the case with best in class ADCs – predominantly incorporating PBD or duocarmycin payloads. These ADCs are hugely problematic to develop, primarily because these payloads are very hydrophobic and despite only comprising 2% of the ADC, they dramatically effect the propensity to aggregate. Consequently, effective aggregation control solutions are now critical – without which such ADCs can’t be manufactured.

Control of aggregation can be achieved by physically segregating antibodies from each other during the critical conjugation steps. ADC Bio has developed its proprietary “Lock-Release” technology over the last six years. The technology platform allows immobilisation of antibodies onto a solid-phase support, thereby segregating them and preventing aggregation during the critical conjugation steps. Following conjugation to payload, the ADCs are subsequently released into an optimal formulation containing stabilizing excipients that suppress aggregation.

The ADC pipeline faces a quality issue bottleneck which, if not addressed, will prevent drugs reaching the market. There is an urgent need to adopt techniques that prevent the formation of soluble high-molecular weight (HMG) aggregate in ADCs – thereby preventing severe adverse immune responses in patients that renders drugs unusable.

Turning to the early stages of ADC development, scientists require much greater certainty that read-outs from initial in vitro panels are accurate and reliably predicative of in vivo efficacy and safety. Consequently, technology is needed that guarantees that ADCs are free of residuals, in particular free cytotoxic payloads and solvents  – each of which impact negatively on in vitro assays.

The only commercially available system that controls aggregation at source and that is scaleable and capable of meeting the regulatory requirements of Good Manufacturing Practice (GMP) required to produce materials for use in human clinical trials is the Company’s Lock-release platform – a fast, simple, cost efficient and robust system that guarantees the consistent production of high quality, purified bulk drug substance.

“Effective aggregation control technologies are now essential and can be the difference between whether an ADC makes it to the market as a commercially viable product or fails. Indeed, much of our future customer base will come in as the industry realizes that not all CDMOs are equal and you require not just facilities, but also highly specialist technologies when it comes to aggregation control” commented Charlie Johnson, CEO of ADC Bio. 

He added: “We’re coming to the ADC market from a completely different direction – we are not an all purpose CDMO. We realized that there was a problem and consequently developed a proprietary technology. As a result, we are expanding our facilities to meet ADC production demand.”

Lock-Release will ultimately provide better patient outcomes by allowing tumor-biology to select the best available payloads and ADC formats rather than allowing manufacturability to determine what products are possible. Manufacturers and innovators will be able to select the optimal ADC concepts that can be manufactured to a meaningful scale – making the best and most efficacious ADC products possible. It is a step change technology that is set to provide the market with the best process solutions.