Read Act 1: The great reappearing act: Antibody-drug conjugates' triumphant return
Armed with improved linker tech, companies were able to further refine their drug’s payloads. In some cases, the ADC construct itself was able to breathe new life into failed toxins.
In the early ‘90s, Daiichi began developing a topoisomerase I (Topo I) inhibitor known as exatecan mesylate as a cancer treatment. Ultimately, the inhibitor failed to demonstrate survival or clinical benefit in a phase 3 study, so development was discontinued. Researchers then turned their attention to investigating the potential of a derivative, known as DXd, as a possible payload for trastuzumab using ADC technology.
The resulting drug, which was jointly commercialized by Daiichi Sankyo and AstraZeneca, was first approved as Enhertu in late 2019 for HER2-positive metastatic breast cancer. Now a blockbuster racking up worldwide sales of $1.3 billion last year, the drug has approvals across several types of cancer.
Importantly, Enhertu was the first drug to break the mold on cytotoxic agents, relying on DXd as its payload. While Topo I inhibitors are actually less potent than the payloads used for first generation ADCs, Daiichi Sankyo’s proprietary DXd technology is able to optimize the ADC through both its payload and linker. The technology provides flexibility to adapt the drug-to-antibody ratio — the number of DXd molecules conjugated per antibody — to the construct necessary for ideal efficacy and safety.
“Enhertu is an example of re-purposing of a failed toxin, by adding a novel linker, and attaching it to a targeting antibody. The ADC concept overcame the limitations of the toxin when it was previously trialed as a stand-alone small molecule,” says Colin McKee, head of Technical Services, Sterling Pharma Solutions.
Sterling, a UK-based CDMO, jumped into the ADC space headfirst with a 2020 partnership with bioconjugation services provider ADC Biotechnology, and then solidified its presence by buying the company a year later. Sterling has since invested over $5 million into the Deeside, UK facility it picked up in the acquisition.
The Sterling/ADC Bio team spent a decade working with Switzerland-based drugmaker, ADC Therapeutics, on multiple ADCs, including its lead asset, a CD19-directed antibody conjugated with a DNA cross-linking pyrrolobenzodiazepine (PBD) dimer. The drug, branded Zynlonta, was approved in 2021 for adults with relapsed or refractory large B-cell lymphoma.
“The approval of our first product just 10 years after the company was founded was done with our PBD payload technology, which is the one of the most potent payloads. The level of potency makes it difficult to work with and we are the only company that has done it successfully,” says Ameet Mallik, chief executive officer of ADC Therapeutics.
ADC Therapeutics’ proprietary payload platform facilitates the use of a novel class of highly potent PBD dimer toxins, which are released inside tumor cells and subsequently bind to the cell’s DNA, causing covalent cross-links. Because the dimers, which are compounds formed by joining two molecules together, do not distort the tumor cell’s DNA structure, the cross-links are invisible to the cell’s repair mechanisms and thus are able to covertly continue to cause tumor cell death.
“As an industry, we’ve been working with a small set of payloads, but in the future there will be more payloads using existing technology in new ways — or we’ll have truly novel payloads,” says Mallik.
The efficacy and safety of an ADC is impacted by each of the drug’s components — its payload, mAb and linker — as well as the conjugation method that brings it all together. While this complicates development, refinement facilitates the creation of better ADCs.
“In order to make meaningful improvements in the performance of next generation ADCs, it’s really important to try to optimize each aspect of the overall construct,” says Pyramid’s Lestini. “A highly differentiated ADC is truly more than the sum of its parts.”
Complex routines
While the anecdote of Paul Ehrlich’s magic bullet theory finally coming to fruition is a fun way of telling the ADC story, complexity — not magic — dominates the ADC discussion. And despite significant advances, the reality is the entire ADC life cycle is fraught with obstacles.
According to Matthias Bucerius, head of Synthesis & ADC CDMO at MilliporeSigma, success in ADCs requires expertise in several different areas. “And that alone gives ADCs a higher risk profile than your standard small molecule or your standard monoclonal antibody. It’s also what explains some of the attrition specifically in the earlier days,” says Bucerius.
As the CDMO arm of Germany’s Merck KGaA and an established leader in the ADC space, MilliporeSigma has played a role in close to half of the ADCs currently on the market. Last year, the company unveiled a $65 million expansion, adding a 70,000-square-foot facility near its Madison, Wisconsin plant to boost production of highly potent active pharmaceutical ingredients (HPAPIs).
The HPAPIs needed to make the small molecules — the payload portion of the ADC — require facility design and engineering beyond what is needed for traditional biologics. Safe handling also demands specialized training.
“The payloads used in ADCs can be a hundred times more potent than standard cancer therapeutics. That requires a very specific knowledge of how to handle these substances in a safe manner and protect employees and the environment,” says Lonza’s Bertholjotti.
Proficiency in both small and large molecule manufacturing, as well as capabilities in conjugation, analytical testing and drug filling is necessary, which makes for a complicated — and expensive — supply chain. Bringing it together reliably is a huge undertaking — and one that most pharma companies can’t or won’t endeavor to do on their own.
“To build up the expertise along the entire value chain is really complex and requires a lot of in-house expertise. This explains why a lot of companies choose to outsource a significant portion of the ADC supply chain to CDMOs,” says Bucerius.
CDMOs have not only risen to the occasion but have dominated the ADC model — it’s currently estimated that as much as 80% of ADC manufacturing operations are outsourced. By 2030, the ADC contract manufacturing market is expected to reach $3 billion.
“ADC CDMOs have built the specialist manufacturing facilities designed to achieve containment levels that are typically associated with HPAPI manufacturing, but still meet the CGMP requirements for biologics,” says Sterling’s McKee. “These facilities are a balance between containment and product protection. There are a lot of engineering and operational controls such as single pass air, HEPA filtration on both inlet and extract, use of isolators and other containment types of technology, single muse or product dedicated equipment trains.”
Not only does outsourcing save pharma companies from having to invest in expensive facilities and equipment, but established CDMOs are able to sync activities between the different unit operations, alleviating the supply chain complexity for their pharma clients.
Continue reading Act 3 of our 3-part series: ADCs light up the stage
