A ‘downstream bioconjugation‘ method may present a new model in antibody-drug conjugate development and manufacturing. In contrast to the existing approaches – which undertake bioconjugation after both the monoclonal antibodies and cytotoxic payload have been manufactured – this new approach moves the conjugation step into the later stages of the downstream processing (DSP), with conjugation and antibody purification carried out concurrently.
“The major benefit, and the reason this approach will prove so disruptive, is that it will save several months of manufacturing time and up to 25% of the overall costs. But it will require much of the industry, with its current ingrained manufacturing methods, to reevaluate exactly how it structures the supply chain that often uses three CMOs,” commented Charlie Johnson, CEO of ADC Biotechnology, the company developing this approach.
Using this ‘downstream bioconjugation’ approach, potentially means less time at the antibody manufacturer (i.e. less time in traditional downstream processing), with the remaining downstream processing and conjugation service both transferring to the bioconjugation CMO. The result is a refined, simpler and much more efficient system – saving up to three months of development time and resources plus creating large cost savings.
Using ADC Bio’s method, the starting point for conjugation will no longer be post-creation of purified antibodies and will instead begin with antibody supernatants. This pproach forgoes the need for extensive chromatographic purification techniques to deliver purified antibody.
The production technique – yet to be formally named – will also remove the need for expensive Protein A resins, instead replacing them with capture resins that are at the heart of the ADC Bio’s ‘Lock-Release’ technology platform – a platform 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.
In ADC manufacturing, the Protein A capture step is the most costly in downstream processing, delivering semi-purified antibody. Now, starting from antibody supernatant, ADC Bio’s approach will see their patented ‘Lock-Release’ technology facilitate both the antibody capture step and subsequent conjugation to the ADC payload – essentially replacing the Protein A resin and assembling the ADC in an efficient manner.
The subsequent viral inactivation, removal and polishing will then occur post-conjugation.
The benefits of eliminating the need for proteinaceous A & G resins extends beyond substantial cost savings. Incidental leaching of these proteins from their purification media increases the impurities in a biopharmaceutical drug product – all of which have to be removed in subsequent chromatography polishing steps before an antibody can be used for any therapeutic application. Moreover, Protein A is known to cause immunogenic responses in humans and has proven toxic in a number of clinical studies – thus its removal is mandatory.
“In essence, we are telescoping antibody DSP and conjugation, providing just one set of analytical development and release processes, whilst bringing in the use of much more cost effective and safer resins. We have already successfully piloted our new development process in a number of applications,” Johnson said.
“As the next step, we have just launched our Specialist Process Innovation Group – which will be responsible for fostering all further technological innovations moving forwards – with its first project being to validate our new downstream conjugation approach over the course of the next 18 months,” he concluded.