Stresses during the purification, processing and storage can change the structure of many proteins, such as antibodies which are marginally stable in solution, giving them a tendency to aggregate. This can lead to eventual precipitation of the protein out of solution which may result in the loss of a large proportion of the drug during purification as it forms part of the aggregate composition, or, in some circumstances, contamination of an entire batch making it unusable.
“Aggregation is like making an omelette from an egg. Once you start to form the omelette you can’t reverse the process to get back to the egg form,” Charlie Johnson, CEO of ADC Bio, described the process to Biopharma-Reporter.
And this problem is more pronounced in antibody-drug conjugates (ADCs), he continued, as manufacturing such therapies involve a series of activation, conjugation, buffer exchange, or other handling steps to yield the molecule from the antibody and drug-linker starting materials.
“All ADCs are prone to aggregation to some degree,” Johnson told Biopharma-Reporter. But while this risk is minimised with ADCs already on the market through extensive process development phases and finely-tuned purification methods, next-generation ADCs are at risk due increasingly potent payloads.
Adcetris and Kadcyla, which have been on the market for a number of years, use drug-linker payloads based on auristatins and maytansines respectively. “These drug-linkers are prone to aggregation as they are intrinsically hydrophobic in nature,” said Johnson.
However, these are established, well understood and less problematic than the new classes of drug-linker payloads emerging from development such as duocarmycin, pyrollebenzodiazepene (PBD) dimers and alpha-amanitin.
“These new payloads are much more hydrophobic in nature and have inherent solubility issues in water buffered systems, resulting in a higher propensity to aggregate.”
Over the past few years, there have been a number of sizeable investments by contract development and manufacturing organisations (CDMOs) in payload-linker technologies.
But Johnson told us many of these firms are unprepared for the aggregation issues associated with the upcoming ‘best in class’ payloads, and do not have the level of control of aggregation that his firm offers through its Lock-Release technology platform.
The platform, which Johnson claims is the only commercially available system that controls aggregation at source and that is scaleable and GMP compliant separates the antibodies from each other through binding to a solid phase bead.
The manipulation of the antibody, the introduction of the drug-linker and the formation of the ADC are all performed upon the bead and all ADC molecules are spatially separated from each other, he explained.
As such, Johnson said he expected strong demand for the tech as industry looks to overcome ADC aggregation issues.
“ADC Bio’s GMP facility and unique offering has two-fold advantages. It will accommodate clients who have existing ADC processes based upon traditional solution phase manufacturing but what gives us a clear market edge is that our facility offers the manufacture of ADCs via our unique Lock-Release technology for controlling aggregate and further delivering process and economic advantages.”