The COVID-19 crisis has had a devastating impact on populations across the world and caused the death of hundreds of thousands of people. The Antibody Society spoke to Dr. Jacob Glanville, CEO and President of Distributed Bio, Inc. to learn how his company has approached the development of new antibody therapeutics against the SARS-CoV-2 Coronavirus. He described how the crisis has stimulated innovation that may revolutionize the way we approach antibody discovery and development once the current pandemic is under control.
Dr Glanville explained, “The problem, when we think of every major outbreak, such as Ebola, SARS, MERS, Swine Flu, Avian Flu, is that the time it takes to develop a new drug is too long compared to the speed with which we need it. De novo discovery is too slow.”
To develop antibody therapeutics against COVID-19 as quickly as possible, Distributed Bio identified anti-SARS antibodies from almost 20 years ago that researchers had already shown would neutralize the SARS virus in vitro, protect mice from lethal challenge, and had known crystal structures. These antibodies have been studied extensively but were eventually too late to have an impact on the SARS crisis of 2003. It was Glanville’s idea to take advantage of the detailed functional research already performed on these antibodies and, try to retrofit them to bind to the new version of their original target the virus SARS-CoV-2. For this purpose, Distributed Bio applied their Tumbler technology, a computationally-guided antibody optimization method, capable of producing a library of billions of variants of individual antibodies exploring variations of all six complementarity-determining regions simultaneously.
“The novel coronavirus has around 74% homology in identity with the SARS receptor binding domain. I knew exactly how similar they were to the novel coronavirus as we had crystal structures of the SARS epitope. I believed that if we took five anti-SARS antibodies, there was going to be a pretty good chance that we would be able to adapt them to be a potent medicine against COVID-19,” said Glanville. “We already knew that they had the correct function, that they bound the right epitope in the right orientation with the right elbow angles. I believed that we could optimize them and enhance their affinity by making billions of versions of the antibodies within the library,” he continued.
According to Glanville, this is crucially important because historically, with outbreaks such as Ebola, the first antibodies launched were essentially prototypes with low potency or had inferior characteristics such as poor thermostability. It was the best-in-class not the first antibody that was successful, ultimately.
Distributed Bio were able to adapt all five antibodies in just nine weeks, a testament to the remarkable speed of these novel technologies. They sent a set of the most promising candidates to five laboratories which independently confirmed their ability to bind to the new SARS-CoV-2. The company then selected the two most potent antibodies for in-vivo testing, and two laboratories confirmed independently that both candidates protected healthy, as well as immuno-compromised animals using hamster models.
Glanville believes the antibody discovery world is evolving in this direction. “We are trying to apply a combination of computation and wet-lab experimentation, and we’re getting the hybrid advantage of the two technologies. This is the best solution to the challenge of antibody development,” he said.
“Some groups skipped the traditional safety and toxicity studies, partly because the animal models had not been established at the beginning of the year. The Food and Drug Administration (FDA) generally considers a two-week study in rats to be sufficient for an antibody against a “non-self” target. We chose not to skip these studies because I don’t think it would have saved us that much time. Furthermore, the FDA is allowing very efficient clinical studies that start with Phase 1/2, but then transition through an adaptive design into a Phase 3 study. These are like a seamless, single human study that allows you to jump through the phases very efficiently. We believed we had an innovative and efficient study design, but then we learned that other groups were doing the same thing and the industry was converging on a common strategy to develop medicines efficiently.”
Glanville believes that one area where new approaches to antibody development is needed is in the field of manufacturing. Conventional approaches to biologics manufacturing can have long development times, high costs and provide limited access to available capacity. He explains that some groups attempted to accelerate manufacturing process development by using stable transfectant pools rather than isolating a single Chinese hamster ovary clone.
“My understanding of the FDA’s position is that they would allow this approach up until Phase 1, but then require the use of fully validated material from a single clone from Phase 2 onwards. It doesn’t really help because the clinical trials can be set-up so efficiently that it doesn’t save much time,” Glanville said.
The current crisis does, however, appear to be triggering significant innovation in this area. For example, when Glanville spoke to the Bill and Melinda Gates Foundation, he found the organization to be very interested in the possibility of using yeast as an alternative manufacturing platform to mammalian cell culture. “Their major concern is that even if we have a good antibody, we are not going to be able to make enough of it using cell culture systems using capacity in the US or globally. Exploring alternative manufacturing systems makes a lot of sense,” he said.
For their part, Distributed Bio are working with a contract manufacturing and development organization for the production of their anti-SARS-CoV-2 monoclonal antibodies. It is normally a 12-month process to produce GMP material from cell culture for first-in-human trials, but companies have been able to reduce this timeline during the crisis by carrying risk and performing development activities in parallel to one another.
Unusually, Distributed Bio has chosen to progress an alternative manufacturing approach in parallel with outsourcing cell culture development by choosing to partner with SwiftScale Biologics. Distributed Bio and SwiftScale will adapt the antibodies Distributed Bio has developed into a scFv-Fc format, which can be expressed in SwiftScale Biologic’s bacterial production platform. This could allow them to reach the clinic in as little as 4 to 5 months. Glanville explained that while it takes a long time to build a new manufacturing facility it can be relatively quick to repurpose one and have it certified to GMP. Utilizing repurposed bacterial production capacity would avoid delays in accessing cell culture capacity, which is in high demand at the present time. Glanville remarked “The limitation is that the bacterial expression of sc-Fv-Fc antibodies is more novel and has not yet gone through an approval process with the FDA. The FDA has approved biologics expressed in bacterial systems, however, and also a number of Fc-fusion proteins.” He believes the agency should look favourably on an approach that combines these technologies.
“It will be great for the entire industry if new manufacturing technologies get approved through product launches during this crisis because it will allow us to use that faster technology in the future,” said Glanville.
“This could be one of the beneficial things that happens as a consequence of this terrible pandemic. It is the most serious medical crisis of our lifetimes and it has fuelled a tremendous amount of innovation. We have challenged all of our medicine engineering technologies so that, unlike ten years ago, when it would take over a year or maybe even two to discover an antibody and then optimize it, it can now take just three months. That’s very exciting and it lowers the activation bar for how hard it is to make new medicines. It used to take a further four or five years to develop an antibody and prepare for clinical trials. People used to talk about it being a ten-year process, but I think what we’re learning from the crisis all the ways you can cut out the fat from the process and create lean programmes that can move medicines through the clinic faster.”
“We’re in this golden age of biotechnology with amazing new single-cell characterization technologies, rapid computationally-guided optimization technologies and better manufacturing. I think that this is going to be the moment where we catch up with these pathogens because we’re tired of them winning all the time. This time the industry is going to make the medicines in time to address the outbreak.”
“I also think we should aim our sights higher and realise that with broadly neutralizing antibodies and broad-spectrum vaccines we could start making inroads to win, not just the individual battles, but also the forever-wars against these pathogens. We can use these technologies against Coronaviruses but also against Filoviruses and Flaviviruses. This is what I expect to see happen because there is so much money and attention being poured into these concepts right now. Having a series of broad-spectrum therapeutics against pathogens will give rise to a more pathogen-free humanity for our children. This could be accomplished within our lifetime as a direct consequence of the research and technological advances that this virus has forced upon our community.”
The Antibody Society would like to thank Dr Glanville for his time during the interview. Distributed Bio is a company comprised of computational immuno-engineers. Its mission is to create breakthrough technologies to drug previously challenging targets (GPCRs, ion channels, pMHC complexes, condition-specific binders, anti-idiotypes, and broadly neutralizing viral epitopes). In monoclonal therapeutics, the integration of computational immunology, bioengineering and robotics has enabled it to create a pipeline of molecules with unprecedented biophysical properties, while also supporting all of its partners with thousands of high affinity developable antibodies against any drug target of interest. In vaccine science, Distributed Bio’s Centivax technology is producing broad-spectrum vaccines against rapidly mutating pathogens like influenza and HIV. For more information visit distributedbio.com.