Supporting The Next Generation Of ADCs
By Tyler Menichiello, Chief Editor, Bioprocess Online
Antibody-drug conjugates (ADCs) are an exciting class of therapeutics that combine powerful cytotoxic drugs with highly specific, cancer-targeting antibodies — at least historically. Nowadays, ADCs are advancing beyond oncology and into even broader disease areas (e.g., immunotherapy), thanks to innovations in biochemistry and molecular design. (Though, they are still predominantly being developed for oncology.)
The ADCs in development today generally have more sophisticated, or at the very least, more refined constructs than their predecessors did, geared towards maximizing efficacy and minimizing off-target toxicity. While the potential of these newer constructs is promising, their complexity can present unique challenges in terms of development and manufacturing.
What Innovations Are Enabling Next-Gen ADCs?
Better linkers — i.e., linkers with improved stability profiles or conditional cleavage — can reduce off-target toxicity and improve ADC safety, while site-specific conjugation allows for greater molecular homogeneity. This improved, specific conjugation helped shift production away from random drug-antibody ratio (DAR) loading to defined DAR loading, said Shor. Earlier ADCs often used endogenous cysteines or lysines as conjugation points, which generally led to more heterogenous DAR mixtures, according to Rosenberg. “That probably did lead to higher failure rates of these first ADCs that went into the clinic,” he said.
“It takes a long time to develop a new payload with a new mechanism of action,” said Rosenberg, “years of early research and preclinical work to get them ready for scale-up and clinical trial testing.” Aside from validating the MOA, this entails figuring out how to conjugate the payload to the antibody and addressing any potential toxicities or therapeutic window issues, he explained. While many in the industry are currently focused on a relatively small number of targets, Rosenberg believes that new targets will emerge over time, leading to more innovation in payloads.
“In order to enable different payloads, we actually need better linkers,” Torres added, particularly to facilitate dual or multi-payload constructs. “In my view, they’re hand-in-hand,” he said. “The wrong linker can kill an asset. The right linker can help unlock the potential of that payload or that novel target.”
How Advanced ADC Constructs Complicate CMC
Continuous innovation was the theme of this ADC panel discussion, and indeed a throughline in the industry itself. “A lot of times, you’re building off of what was done before,” said Rosenberg. Biopharmaceutical development is expensive enough without having to re-invent the wheel, so if a company is bringing forward a new ADC with a novel target or payload, they will likely complement that with an existing linker or conjugation method that’s been validated.
When it comes to ADC constructs, innovation needs to be weighed and considered against timelines. “If the linker-payload is new or novel, it may take longer to develop the process,” Rosenberg explained. The manufacturing process and supporting analytics are all impacted when incorporating innovation in your ADC design, he said.
Weighing these innovations means considering their associated risks. “There’s certain things that you can de-risk, and that’s where you want to spend some time,” Torres explained. “But ultimately, you’ve got to go through that process of finding that final TPP (target product profile) for that drug that you want to unlock.” This requires extensive testing and validation through “as many assays as you can,” said Torres, which is what smaller companies really need to think through. “Not all of us are a BMS or Pfizer with large budgets to do these things,” he said.
In terms of actually making innovative ADCs, the novel aspects of their manufacturing also need to be considered, said Torres. “In the case of newer conjugation enzymes, there’s a whole host of new pieces or reagents that need to be validated,” he explained. These need to be sourced and “pressure tested” in terms of their scalability.
An ADC built with a multi-specific antibody will present different manufacturing challenges than a traditional mAb process would, Rosenberg explained (e.g., aggregation). A process that relies on enzymatic conjugation may require totally different scale of enzyme production, in addition to the conjugation itself, said Shor.
Novel constructs or manufacturing processes are cool, but can available CDMOs make them under GMP? These aspects of the process and how they relate to the COGs need to be thought through when planning an ADC platform, said Torres.
Navigating Sourcing And Global Manufacturing Challenges
While the cost of de-risking newer ADC constructs is a primary consideration for smaller companies, so are the logistics of sourcing and manufacturing, said Shor. The geographical separation of quality CDMOs that are able to provide the three main components at a GMP scale presents a significant challenge for scaled commercial manufacturing, he explained.
“One of the biggest challenges in CMC and supply chain is something that’s sort of new to us in the last few years, and that’s the geopolitical risks or concerns.” Rosenberg said. “You never used to hear that concern, really, 10 or 15 years ago.”
The majority of ADCs are made by contract manufacturers, of which there are a limited number and are mostly found in Asian countries, Rosenberg explained. Navigating this CDMO landscape and managing the associated risks has become a common theme in the last few years.
Focus On Potency Assays
Analytical tools and methods are advancing right alongside ADCs, allowing for more precise characterization and structural insight. There have been huge improvements with methods like high-performance liquid chromatography (HPLC) and mass spectrometry, said Rosenberg. He thinks these improvements will continue, achieving greater sensitivity and higher throughput speed that will afford a better understanding of the heterogeneity of ADCs.
“One area of particular note developing ADCs is the potency assay, which is often a cell-based cytotoxicity assay,” Rosenberg added. These assays often take time to develop and are dependent on the responsiveness of the target cell line, he explained. Moving forward, Rosenberg thinks there will be more innovation in this space in order to streamline development.
One thing to consider for these potency assays is the potential challenge in licensing certain cell lines, Torres added. “It’s one thing to be able to get access to a cell line just to do in vitro screenings,” he said, “but to have it as part of your potency assay, there’s potentially different licenses and things that you need for those cell lines that may not be quick to get.”
In some cases, a CDMO may have that challenge already worked out for you, and it may not be an issue. In other cases, especially with a novel target or rare cell line, developers need to start thinking very early on about securing their cell lines for use in potency assays, Torres said. “It may take time just to even get the contracts and licensing done to incorporate it.”
For more of our panelists’ thoughtful commentary on analytical development for ADCs, watch the full segment from our recent Bioprocess Online Live event here.
You can watch the entire event for free thanks to our event sponsor, Cytiva. On that web page, you’ll also find links to other in-depth segments from the discussion. We host these types of panel discussions regularly throughout the year, so stay tuned to Bioprocess Online for more expert insights on topics ranging from CMC to MSAT and everything in between.