ADC Targets Fail Because of Aggregation Problems

Published on: 

ADC Bio experts warn of impending problems in the ADC pipeline with millions wasted in development costs.

As more full-service CDMOs begin to invest in conjugation and ADC facilities, experts from ADC Biotechnology (ADC Bio) have warned that best-in-class antibody-drug conjugates (ADCs) are being overlooked because of critical aggregation control problems. As a result, companies are finding it difficult to develop economically viable products that are capable of working successfully in clinical testing.

“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 commercialized 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 commercialize optimal ADC therapeutics and that is ultimately a failure to patients desperately in need of new life-saving therapies.”

ADCs, predominantly those incorporating pyrrolobenzodiazepines (PBD) or duocarmycin payloads, are hugely problematic to develop. This is primarily because these payloads are very hydrophobic and despite only comprising 2% of the ADC, they dramatically affect the propensity to aggregate. Effective aggregation control solutions are, therefore, crucial, 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’s proprietary “Lock-Release” technology allows immobilization 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 bottleneck that, if not addressed, will prevent drugs from reaching the market. There is an urgent need to adopt techniques that prevent the formation of soluble high molecular weight (HMG) aggregate in ADCs. These aggregates can trigger severe adverse immune responses in patients, hence rendering the drugs unusable. During the early stages of ADC development, drug developers are looking for greater certainty that the in-vitro data are accurate and reliably predicative of in-vivo efficacy and safety. A technology that guarantees ADCs are free of residuals would benefit drug developers. 


Lock-release is a platform that controls aggregation at its source. The technology is scalable and capable of meeting the regulatory GMP requirements. It ensures 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” said Johnson, who 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 allows tumor-biology to select the best available payloads and ADC formats rather than relying on 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.

Source: ADC Biotechnology