The great reappearing act: Antibody-drug conjugates' triumphant return

Antibody-drug conjugates go by many stage names: ‘trojan horses,’ ‘cancer-seeking missiles,’ ‘armed antibodies’ — and even, ‘magic bullets.’

The latter is a nod to a commonly referenced term coined over 100 years ago by Nobel Prize-winning German scientist Paul Ehrlich, who theorized that it was possible to create disease-seeking chemicals that would selectively target specific pathogenic organisms.

The modern-day application of this theory is artfully simplistic in concept: A cytotoxic agent — or ‘payload’ — is linked to a monoclonal antibody and directed toward a specific cell surface target overexpressed by tumor cells, killing the cancer cells while leaving healthy tissue unharmed. The drugs offer the best of both worlds in cancer care, overcoming the limitations of many current therapies by combining the toxic properties of chemotherapy with the accurate targeting of antibody-based treatments.

But in practice, guiding these cancer-killing bullets from discovery to market has proven to be anything but magic. In fact, many argue that ADCs are the most complex platform available for systemic delivery of anticancer medicines. Success demands scientific and manufacturing deft, optimized technologies and a tightly integrated supply chain.

Looking back on the last five years — which saw the U.S. Food and Drug Administration approve 9 ADCs in oncology — it would be easy to overlook how hard-fought the wins have been in the space.

It started 23 years ago, when Wyeth’s Mylotarg, a CD33-directed antibody and cytotoxic drug conjugate, grabbed the first FDA approval. Many had hoped Mylotarg, which was the first novel drug in 15 years to treat a rare, aggressive type of bone marrow cancer, would open the curtain on a whole new act in oncology treatments. Instead, it revealed some very real obstacles for ADCs.

One place those obstacles became apparent was in the clinical space. According to Citeline data, 57 trials launched between 2000-2015 either ended in failure or were terminated; close to 25% of those trials were phase 3. Approvals slowed and ADCs temporarily faded from the spotlight — but their scientific allure was not forgotten. Facing large patient populations with unmet needs, pharma’s well-funded oncology sector’s relentless search for innovative treatments circled back to the promise of ADCs.

Now, with 13 drugs approved by the FDA, several factors have converged to set the scene for what much of the industry is betting to be antibody-drug conjugates’ triumphant return.

“We’re seeing somewhat of a renaissance in ADCs in oncology for a few important reasons,” says Dr. Brian Lestini, chief executive officer of Pyramid Biosciences.

Pyramid recently signed a $1.2 billion deal with China-based GeneQuantum Healthcare to develop and commercialize an ADC targeting trophoblast cell-surface antigen 2 (Trop2), a protein overexpressed on many tumor cells. Pyramid believes the candidate has the potential to address substantial limitations of current ADCs and unmet needs for patients with Trop2-expressing tumors.

According to Lestini, the combination of several achievements — a better scientific understanding of cancer and biomarkers, modern clinical success, and technology improvements — have contributed to ADCs’ reappearing act.

“ADCs have been clinically proven to drive better outcomes for patients, which provides a foundation for creating next-generation constructs. We have also become much smarter and diversified in developing novel technologies that lead to potentially safer and more effective ADCs,” says Lestini.

With 428 drugs in the pipeline, big-ticket deals dominating the headlines and a market poised to reach over $13 billion by 2026, today’s ADCs may have finally earned their permanent place on the industry stage.

An extended first act

According to Dr. Fred Appelbaum, the story of Mylotarg is “long and unusual.”

Appelbaum, who currently serves as executive vice president of Fred Hutchinson Cancer Center, was a key contributor to the discovery and development of gemtuzumab ozogamicin, which came to be known commercially as Mylotarg.

In the 1980s, after developing an antibody specific to CD33 — a molecule found on the surface of some leukemia cells — researchers at Fred Hutch turned to the well-known antibiotic innovator Lederle Labs for help using the antibody to deliver the potent antibiotic calicheamicin to cancer cells. In 1994, Lederle was acquired by American Home Products, which then rebranded as Wyeth in 2002 — and gemtuzumab ozogamicin went along for the ride.

At the time, patients with acute myeloid leukemia (AML) had few treatment options and often died within months of diagnosis. But while the urgency was big, the potential market was not — AML is rare and accounts for only about 1% of all cancers. As the developing treatment changed hands, researchers like Appelbaum were busy trying to keep drugmakers interested.

“We made frequent trips, first to Pearl River to meet with Lederle/AHP, and then to King of Prussia to meet with Wyeth. The hesitation of the companies was always on the small market they saw for AML,” says Appelbaum. “We argued that it would be a great proof of principle.”

When Mylotarg was approved in 2000, it was in fact for a small subset of patients — those age 60+ with relapsed CD-33-positive AML who were not candidates for other chemotherapy.

The drug was approved under the FDA’s Accelerated Approval program, which mandated a post-market study. According to Appelbaum, the confirmatory study hit several snags, finally launching in 2004. And then it got worse: The drug not only failed to show clinical benefit in the trial but was also associated with a higher death rate as a result of liver toxicity. Pfizer, who had just bought Wyeth in 2009, was left to deal with the fallout.

“It took a very long time to get that single study done, and when it failed to meet its endpoint, the FDA out of frustration asked Pfizer what they were going to do. Pfizer had no prior history with the agent and didn’t want to fight with the FDA, so they simply agreed to remove it,” recalls Appelbaum.

Pfizer voluntarily withdrew Mylotarg from the market in 2010, but the drug continued to provide valuable lessons in the ADC space.

Given the dearth of treatments for AML, clinicians were not willing to give up on Mylotarg. Several academic groups continued to pursue trials, testing the drug in different patient groups in varying dosages, using modified administration schedules. The results from those studies demonstrated that by lowering the dosage and adjusting the dose scheduling, some of the unwanted toxicity could be avoided.

Mylotarg was resubmitted by Pfizer and reapproved by the FDA in 2017, for both adults and children with relapsed/refractory AML, as well as newly diagnosed adult AML patients.

Linking lessons

One of the first routines learned by aspiring magicians, the ‘linking rings’ trick is a magic show rite of passage. For ADCs, improving the design of the chemical linker connecting the mAb to the cytotoxic drug became a similar staple of development routines. 

Mylotarg’s initial off-target toxicity was a common hurdle in the early years of ADCs, but drugmakers found that by refining linker technology, they could better control the release of the toxic payloads.

“The initial products that reached the market like Mylotarg had linkers that were not as stable as they potentially needed to be. And with that, you can imagine if you have an antibody where a very toxic payload is attached and this connection is not fully stable, then it could be released uncontrolled in the bloodstream before that molecule can be internalized in the cancer cell,” says Iwan Bertholjotti, senior director, Commercial Development BioConjugates for Lonza.

And the opposite was also possible: If the linker didn’t cleave the payload once inside the cancer cell, the treatment would be ineffective against the tumor.

“Toxicity is definitely something which took quite a while for the industry to overcome. Toxicity versus therapeutic effect is always a fight,” says Bertholjotti.

The next two ADCs to win FDA approval both demonstrated improvement in linker chemistry. Seattle Genetics’ (now Seagen) Adcetris, which was approved in 2011, was designed with a highly stable cleavable linker. Genentech’s (now Roche) Kadcyla, approved in 2013, utilizes a toxicity-reducing, non-cleavable linker.

Linkers come in two families, cleavable and non-cleavable. Cleavable linkers use an inherent property of the cancer cell to trigger the release of the cytotoxin from the mAb, while non-cleavable linkers don’t have a specific release mechanism, instead relying on the degradation of the mAb once internalized in the cancer cell.

“The next generation of drugs came with more advanced, stable linkers and with that, better control of the side effects. So, products like Adcetris and Kadcyla became blockbusters. And that created an approval of concept for ADCs,” says Bertholjotti.

Switzerland-based Lonza is now one of the biggest suppliers in the ADC space, having been involved on some level with the majority of today’s commercialized ADCs. But Lonza’s foray into ADCs happened in 2006, when the CDMO began working with Genentech on the development of new ADCs.

Continue reading Act 2: The great reappearing act: ADCs' new bag of tricks 

Download the full pdf here