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Speeding the flow with downstream conjugation
WALES, U.K.—While developing new antibody-drug conjugates (ADC) is a regular occurrence for many companies, developing a new method for manufacturing such products is nowhere near as common—and yet that is some of the latest news out of ADC Biotechnology (ADC Bio). The company has announced a “downstream bioconjugation” method that it claims will streamline the manufacturing of ADCs, offering both a faster and simpler production timeline and significant cost savings—up to 25 percent of overall costs, according to ADC Bio CEO Charlie Johnson.
The traditional approach sees bioconjugation taking place after the monoclonal antibody and cytotoxic payload have been manufactured. In addition, current approaches generally use protein A resins for the capture step, which delivers semi-purified antibodies and is the most expensive step in downstream processing.
This new downstream bioconjugation approach will begin with antibody supernatants, rather than conjugation following the creation of purified antibodies. This tactic enables developers to eliminate the need for chromatographic purification techniques to render purified antibodies. All told, the new method could save up to three months of development time.
Johnson says that upon ADC Bio’s creation, the company’s focus was to find a new method of creating ADCs with a starting point of a released antibody, which led to their patented Lock-Release technology. This platform enables ADC Bio to develop ADCs without aggregation issues, he tells DDNews.
“Antibodies are hydrophilic in nature, and very often the payloads that are conjugated to them to form the ADC are hydrophobic,” he explains. “You put those two things together and you can get a problem with aggregation, and that problem can be quite severe—30 percent or more, which needs to be removed from the product before you can administer it to a patient. Even soluble aggregates need to be removed as they can be highly immunogenic when administered. The Lock-Release technique is an effective way of avoiding these aggregation problems.”
That technology will be used in this new production method to aid in the antibody capture step and the conjugation to the ADC payload. The new method will begin with an antibody supernatant. At the point where protein A would traditionally be used, ADC Bio has replaced it with its own mimetic resins.
According to Johnson, “The difference there is that if you tried to do that in the traditional way, using Protein A as the capture resin, you can't then carry out the subsequent conjugation steps, because Protein A is reactive to the payloads and in some cases with other reagents to other reagents that are used to modify the antibody. So we use our mimetic resins that are not susceptible to these unwanted interactions, and we construct the ADC on that resin prior to releasing the ADC, and then subsequently complete the downstream processing steps which would otherwise be in the antibody production process—so for example, viral inactivation, viral removal, polishing and ion exchange steps, which are there predominately to remove any leached Protein A. And we end up at the final product, the ADC, instead of the antibody.”
Leaching from proteinaceous A and G resins is a common issue, ADC Bio noted in a press release, one that increases impurities in drug products and requires their removal in chromatography polishing steps before the antibody is safe for therapeutic use.
“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,” said Johnson. “We have already successfully piloted our new development process in a number of applications.”
Johnson tells DDNews that the company has established the Specialist Process Innovation Group to assess the viability of its new conjugation process compared to current standards.
“The aims of this group will be proof of concept, to demonstrate that we can take the original antibody production process and graft into it the conjugation process, and that that technically works and that we can recover a sensible amount of product from that process, equivalent to what you would get from a process which is antibody first and then conjugation in a separate step,” he says. “So that’s first and foremost what we’re looking to do—that we can achieve the right quality and the right specifications, and that we can provide a virally safe product as well.
“Our intention would be to do a side-by-side case study comparing the traditional way of doing things—antibody first and then conjugation second at a different service provider—with this truncated production process to demonstrate what productivity and economic advantages are possible, which we believe could be very significant. We intend to complete the technical proof-of-concept work over a period of 12 to 18 months. To do this, we will establish a group internally who have the relevant skills in upstream and downstream antibody processing, and combine that with some of our internal experts on Lock-Release to work on the technical proof of concept.”
“This is not a trivial change that we're proposing here; it's a very, very compelling change. To get the industry away from tried and tested ways of doing things is sometimes a challenging journey, even when the conceptual benefits are compelling,” Johnson acknowledges.