An Antibody Drug Conjugate In Every Garage

By Louis Garguilo, Chief Editor, Outsourced Pharma

The conference took on an old-time carnival atmosphere. At the end of one long day, I imagine a barker with megaphone among the booths: “Step right up. Get your very own look at an antibody drug conjugate platform. Don’t be the last in your neighborhood without an ADC in your garage.” Or maybe it was “in your pipeline.” It definitely was ADCs, though.

Nary a service provider at CPhI Worldwide 2014 in France is without the knowhow to help pharma start-up their antibodies, the platform to build their linkers, or the most reliable production of their payloads.

Pfizer CentreSource, that big pharma’s long-operating and now expanding contract development and manufacturing arm, offers all the parts and production capabilities under one roof. U.S. and European firms are awash in explanations of how they best serve as ADC partners in the complicated process of development, assembly and manufacture. Chinese and India brand-name providers promote shiny new and coming capacity.

All this, according to Barry Littlejohns, president, Advanced Delivery Technologies for Catalent Pharma Solutions, “because big pharma customers are declaring at least one-quarter of their oncology portfolio will be ADCs. It’s the major industry growth area within the overall growing biologics sector.” He adds, “It’s a really great place to be.”

But what place is that really? A habitual questioner of trends and strategy, I’ve landed at Catalent’s booth to inquire into their latest acquisition, Redwood Bioscience Inc., of Emeryville, CA, which, I'm sure you’ve guessed, has what both companies believe is a transformative antibody drug conjugates technology.

This is an opportunity to ask Redwood founder, CSO and president, and now Catalent’s head of R&D for Chemical Biology, David Rabuka, Ph.D., and Littlejohns, about the deal itself, the technology, and the realities behind the ADC frenzy in pharma-land. After all, after years of study, and despite a growing number of ADCs in clinical trials, to date only three ADCs have left the garage for commercial roads, including the first pioneering ADC from the aforementioned Pfizer, which unfortunately ended in a recall in the U.S.

The Deal And The Technology

Rabuka, boyish-looking, bespectacled and with a professorial skill to provide clear explanations, points out it was Redwood that first found its eventual acquirer. “We initially reached out to Catalent because of their proprietary GPEx [cell line expression system] technology. They ended up looking back at our technology, beginning an interesting dynamic. Both parties saw the synergies embedded. It is a real cool story.”

We’ll get into specifics of the Redwood technology in a moment, but here, too, readers can intuit it has to do with linkers and the assembly of ADCs. Antibodies are seemingly becoming commodity-like; cytotoxics and other cancer-targeting drugs—existing and in various stages of development—are abundant; but while on the increase, linkers and the technology of assembly and customization per ADC appears to be the real key as we head towards the end of 2014.

But before all that, with the delicacy of a caged bull, I ask Rabuka: “Why sell to a service provider, and not potentially get a larger payoff from big pharma? Did you miss out on a life on a Hawaiian beach?”

“No,” he replies directly after some laughter amongst the three of us. “There is a relationship here. Over the last three years we’ve seen an extraordinary synergy between the technologies Redwood has evolved, and the technologies and services within the Catalent organization.” (And, by the way, he adds he could do research in Hawaii just as well.)

“Our approach,” Rabuka continues, “has always been to springboard the technology, enable the development of drugs from multiple angles. This is not a one-shot-on-goal, or one company’s, technology. We’ve never envisioned ourselves that way. This is a real fit in how we wanted to get our technology as widely distributed, into as many clinical trials, as possible.”

Redwood was spun out of the University of California, Berkeley, where Rabuka did his Ph.D. under Professor Carolyn Bertozzi, who has dedicated her career to “thinking about ways to assemble small molecules and proteins,” according to Rabuka.

Littlejohns says, “In terms of why this is different for us and the market, we have now brought in a technology that can make products better and increases applications. Historically, we have had technology to make a more stable product, make it faster with a better yield, but Redwood’s technology by the use of this linker system and the freedom to work with many toxins, enables us to help pharma with new efficacious treatments.”

The technology has been dubbed the SMARTag Antibody-Drug Conjugate (ADC) technology platform. It has achieved “in vivo and in vitro proof of concept milestones, recent compelling in vivo toxicology data, and strong customer interest,” according to a press release from October 2. The technology is said to enable the generation of homogenous bio-conjugates engineered to improve performance and facilitate manufacturing. Combined with Catalent’s GPEx cell line expression system, the two companies believe they can develop more and better biologics treatments.

Rabuka describes this in the simplest of terms. “We have built out a toolkit for full assembly independent of the components. If a drug company says they would like to assemble an ADC a certain way, we say here is how.”

That assembly will take place at two locations, with the biologics primarily done at Catalent’s Madison site, and the chemistry conjugation pieces developed and executed in California, where Rabuka and his team of 16 employees will continue to work.

I ask Rabuka if the IP is such that, and the biology-chemistry streamlined enough so that pharma and other licensees of the technology can do the work in their own labs.

“So that is a great question,” he says thoughtfully. “Ideally, we do want our system to be simple and robust enough for that kind of transfer. But like a lot of people think they can assemble a car, there really are very few who can fully assemble a BMW. You have to bring in the people and have the right instrumentation.”

“At the same time, it’s not so esoteric that customers don’t understand or appreciate the value. There is special knowledge, but we believe simple and flexible is a part of the value,” he says.

According to Rabuka, Redwood was founded on the principle you could assemble conjugates with the control and chemical precision that a medicinal chemist approaches a scaffold for a small molecule drug.

“We ended up with a series of pieces, for example A through D, to assemble everything. I’ll call A the protein, D the payload, and all in between the linker stuff. We have systematically worked from A through D for an entire package that is fully proprietary. That includes linker libraries and conjugation pieces, and by that I mean the sticky bits, the Velcro piece you need to stick on to your protein. We’ve developed our own sticky bits. We have freedom to operate and significantly improved upon the more traditional approaches people have taken to make conjugates.”

Real Power Or Just Loud Engines?

Are we really on the cusp of a breakout in this area—with major participation from providers and biotechs as well as pharma itself—of drug development, particularly for cancer patients? Why haven’t we seen more success already?

“Yes, only three ADCs have been approved to date,” says Rabuka quickly, “but this is going to happen. You are looking at a historical evolution of the assembly of very complicated molecules.”

“In fact, in my opinion the Mylotarg story is a good one,” he continues, referring to the first approved, but later taken off the U.S. market, ADC for acute myelogenous leukemia, from Pfizer. “They had a good target, and an interesting toxin. It’s just that the other tools weren’t quite there yet. It has taken 15 years of evolution for people to start to figure out how to assemble stuff.”

Rabuka continues: “Seattle Genetics, ImmunoGen, Genentech, the Medarex folks initially, all started to think about the toolkit. It is now reaching a critical mass. Of the three ADCs, two have been approved in the last year and a half. There has been a long evolution of ADCs, covering a hundred years. For almost all history, the idea was way ahead of the tools to assemble.”

“So,” he adds, “we are standing on the shoulders of giants. We have taken that body of knowledge and expanded and significantly improved on it in terms of stability, reproducibility, reliability. We are seeing ADCs with better efficacy and tolerability. There will be many drugs on the market in the future, I believe.”

A closing note is Catalent’s model, if it is such that new technology begets or attracts more new technology, appears to be working. Now a public company, we will be able to measure results more precisely. The Redwood technology, indeed the entire ADC story, is still unfolding. Catalent got a platform into its garage; no reason to think more in the neighborhood won’t follow. For patients worldwide with various cancers, and the success of the pharma industry overall, more ADCs cruising the commercial streets will be a great sight.