Antibodies, Linkers, An Uber, And John Wick

By Matthew Pillar, Editor, Bioprocess Online

In 2018, five co-development deals, an option agreement, and a licensing deal constituted the entirety of antibody-drug conjugate (ADC) market activity. The total value of those deals was pegged at less than $20 billion.

Last year, DeciBio tracked 76 ADC deals collectively valued at more than $117 billion.

That’s a breathtaking flurry of activity for a therapeutic concept first described in the early 1900s, not materialized until the early 1960s, not clinically tested until the early 1980s, and besieged by setbacks well beyond the first FDA approval in 2000. That approval of gemtuzumab ozogamicin (Mylotarg), only extended the beleaguered development reputation of ADCs to the market. Pfizer withdrew the drug in 2010 at the behest of the FDA, after a Phase III comparative controlled trial demonstrated that the gemtuzumab combination therapy group’s fatal toxicity rate was about five times that of the standard therapy group. It was a spectacle of the inherent challenge in ADC development and manufacturing: maintaining payload control via very sophisticated linker and conjugation technology.

Mylotarg came back on the market in 2017 after Pfizer adjusted its acid-labile linker technology and dosing strategy in yet another Phase 3 trial. In that study, complete response was 6% higher in the Mylotarg group, and 2-year event-free survival was nearly 24% higher in the drugged group (40.8%) than in the control group (17.1%). Turns out that fractionated doses of the drug enabled more cumulative delivery to the target, and that, while Mylotarg was still causing more than four times the hematological toxicity than observed in the control group, that toxicity risk wasn’t so severe as to increase the risk of death.

This illustration of the challenges faced by ADC developers after a hundred-year history with the basic concept of the drug makes the recent billion-dollar bets on the modality look all the more dramatic. What gives? Where’s all this confidence coming from?

Logistical Accuracy Advances Underpin ADC Resurgence

ADC delivery is a nanoscopic study in rideshare logistics. The antibody is like an Uber. The payload is like an Uber passenger who happens to be a good guy with a propensity to kill bad guys, a la John Wick. A cleavable linker is like the car’s seat belt, door latch, and lock that keep John Wick in place until he needs to make a hasty exit to kill those bad guys.

All parts of the ADC equation must work, but none is more integral to safety, and perhaps efficacy, than the seemingly lowly linker. The seatbelt. In order for the system to work correctly, car and driver (antibody) need to know precisely where to go and how to get there most efficiently. John Wick (payload) needs to stay buckled in until he and the driver are confident they’ve arrived safely at their destination, where Mr. Wick can do his business without hurting innocent people (healthy cells). The seat belts, door latches, and locks (chemical or enzymatic bonds, or linkers, which keep payloads secure in transit) need to function properly when John Wick is cued for release – no later, and no sooner.

Yes, the analogy breaks down a bit. It’s unlikely that John Wick would get an itchy trigger finger if his Uber driver dropped him off a block short of The Continental Hotel. Cytotoxic payloads released too soon, on the other hand, can wreak in vivo havoc on healthy cells. Biological and chemical engineers made little headway on that big problem for decades, but recent advances in their understanding of the tumor microenvironment and the chemical and physical properties of the linker have improved the linker’s ability to maintain stability in the bloodstream—the interstate highway to the tumor—and more efficiently cleave off where the payloads they secure have work to do. In the crude Uber analogy, they’ve re-engineered the seatbelts, door latches, and locks that keep John Wick where he belongs in transit.

Chemistry, Physics, And Biology Unloaded On Linkers

In ADCs, the linker is everything. That’s why a cottage industry of dedicated linker technology companies have sprung up to support the hundred-billion-dollar-plus market. Engineers have constructed pH-induced chemical linkers that are hydrolyzed within acidic early endosomes in the tumor microenvironment, or in other cases reduced by intracellular thiols such as glutathione, which are generally elevated in cancer cells. Similarly, enzyme-cleavable linkers, which constitute the bulk of those used in approved ADCs, typically consist of dipeptides that are cleavable by lysosomal proteases found in cancer cells. In both cases, the seatbelt won’t unclick until the Uber is in an environment that enables it to unclick.

Non-cleavable linkers, on the other hand, release their cytotoxic payload only after complete lysosomal degradation induced by an added antibody degradation product—a targeted protein degrader conjugated to the antibody. This adds yet another degree of ADC development and manufacturing complexity. In the Uber analogy, driver and car (antibody) arrive at their destination and safely disintegrate, leaving an unscathed John Wick (payload) to do his lethal business with the bad guys.

Now scientists are working on the development of biorthogonal linkers that won’t cleave until a specific nanoparticle is introduced, and photo-sensitive linkers that cleave on exposure to UV light. ADC developers considering the buildout of their arsenals must feel like John Wick in an armory.

If You Dream It, Can You Build It?

I don’t think there’s a biotech discipline that’s churning out more novel therapeutic concepts than the ADC space is right now. These days, it seems there’s nothing we can’t dream of conjugating to an antibody—proteins, enzymes, small molecule chemotherapeutics, radiopharmaceuticals, you name it—and innovators are assessing every chemical, physical, and biological angle to conjugation, linker technology, and payload release.

But big questions remain. Can these dreamy ideas actually be manufactured at scale? And because they require so many moving parts from so many scientific disciplines, what does that manufacturing environment even look like? I’ve talked to ADC CMC (chemistry, manufacturing, and controls) leaders who couldn’t possible overstate how their responsibilities have changed with the advance of this modality. In most cases, they’re spending more time and intellectual capital managing partnership logistics than they are writing CMC packages. None of them are producing their antibodies and their payloads and their linkers within their four walls. Some are doing one piece of it, rarely two, and most are outsourcing the whole kit and kaboodle from multiple partners and overseeing CDMO development from afar. It’s a tough orchestra to conduct. And without an effective linker, the whole show falls to pieces.

Your Linker, Conjugation, And ADC Manufacturing Questions Answered

We’ll spend at least 60 minutes discussing ADC manufacturing challenges and opportunities with a handful of experts on July 9 at 11 AM ET. DeciBio’s Joe Daccache, Ph.D. will be there. He’s a guy who knows this space better than an Uber driver knows the streets. Mythic Therapeutics COO Sandra Poole will be there. I don’t know an exec who’s helped bring an ADC concept to IND faster than she has. Vincerx VP of Medical Affairs Amy Johnson, Ph.D. will be there. Amy knows how to navigate the incredibly fine line between ADC bystander effect (good) and off-target toxicity (bad) as well as anyone in the space. If this incredibly complex and promising modality excites you, I’d like you to join us. It's free, virtual, and interactive, so bring your questions. Register here. I can’t promise you I’ll avoid bad analogies, but I can promise you that my guests will make up for them.