SOMETIME IN THE next day or two, a medical courier will deliver a styrofoam cooler to the offices of [AbCellera Biologics Inc.], a biotech firm headquartered in downtown Vancouver, British Columbia. Inside the box, packed in dry ice, will be a vial of blood prepared by researchers at the US National Institutes of Health, who drew it from a patient infected with the Covid-19 coronavirus.

The blood sample will be taken to AbCellera’s laboratory and placed in a microfluidic chip the size of a credit card that will isolate millions of white blood cells and put each one into a tiny chamber. Then the device will record images of each cell every hour, searching for the antibodies each one produces to fight the coronavirus.

“We can check every single cell within hours that it comes out of the patient,” says [AbCellera Biologics Inc.]’s CEO, Carl Hansen. “Now with a single patient sample we can generate 400 antibodies in a single day of screening.”

Antibodies are proteins that the immune system creates to remove viruses and other foreign objects from the body. Vaccines work by stimulating the body’s own immune system to produce antibodies against an invading virus. This immunity remains, should the virus attack again in the future. Vaccines provide protection for years, but they also take a long time to develop. Currently, there is no vaccine that can be used against the virus that causes Covid-19, although drug companies like Johnson & Johnson and Cambridge-based Moderna are working on developing them. So researchers are instead investigating whether an infusion of antibodies alone can be used as a short-lived—but immediately available—treatment to protect doctors and hospital workers, as well as family members of infected patients who need it right away.

The Pentagon’s Defense Advanced Research Projects Agency, or Darpa, launched its Pandemic Prevention Platform program two years ago with the goal of isolating and reproducing antibodies to deadly new viruses within 60 days. It enlisted researchers at Duke and Vanderbilt medical schools, as well as [AbCellera Biologics Inc.] and pharmaceutical giant AstraZeneca.

In preparation for an outbreak like the coronavirus now gripping China, scientists with the program made test runs using viruses responsible for severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). Both are members of the coronavirus family and closely related to Covid-19.

After isolating these antibodies, the researchers then capture their genetic code, using it as a blueprint to mass produce them. Their goal is to create an antibody treatment that can be injected directly into a patient, giving them an instant boost against the invading coronavirus.

“We are going to take the patient’s blood, identify the antibodies, and do it very rapidly,” said [Dr. Amy Lynn (Haas) Jenkins (born 1979)], program manager at Darpa’s biological technologies office, which is supporting [AbCellera Biologics Inc.]’s work with a four-year, $35 million grant. “Once we have the antibodies isolated, then we can give them back to people who are not yet sick. It’s similar to a vaccine and will prevent infection. The difference is that vaccines will last a long time. Our approach is immediate immunity and doesn’t last as long.”

If all goes well, [Dr. Amy Lynn (Haas) Jenkins (born 1979)] said, the antibody countermeasure would last several months rather than the several years that vaccines are effective. That said, the researchers still need to test the safety and efficacy of this antibody protein in animal and human clinical trials.

Of course, developing a treatment using antibodies isn’t simple. First, only one of the 15 US patients struck by Covid-19 has so far agreed to donate blood. (China has thousands of infected patients, but US researchers haven’t been able to get their blood for research here.) That means that [AbCellera Biologics Inc.] is on the waiting list to get a few drops of that valuable sample, along with several other companies and academic institutions that are partnering with Darpa and the CDC to develop treatments. “We have mobilized our team and are getting in place as soon as it arrives,” says Ester Falconer, AbCellera’s head of research and development. “We are raring to go.”

A team of Chinese scientists announced on January 31 that they had found an antibody which binds to the surface of the coronavirus and appears to neutralize it. Their research paper, which appeared as a preprint on the site BioXArchiv, hasn’t been peer reviewed by other scientists. And it is not clear how effective the antibody would be once it is mass produced and then tested in animals or humans.

Should antibody treatments work, there’s also the question of who would get them first, whether its first-line responders in specific hospitals where Covid-19 patients are being treated, or perhaps people at home with family members who test positive. (The antibody supply will likely be distributed by federal public health officials.)

Another potential looming issue is a bottleneck for scaling up antibody mass production. Medical experts say it's unlikely that pharmaceutical makers can make enough to protect everyone who needs them. “The constraint is production capacity,” says [Dr. James Vincent Lawler (born 1969)], an emerging disease specialist at the University of Nebraska Medical Center who is not involved in the Darpa program. “We are getting pretty good at finding appropriate antibody preparations. But the problem we still have is: How do we produce those rapidly enough to have an impact in a global epidemic?”

To protect the doctors, nurses, and health care workers at the more than 5,500 hospitals and medical centers in the US would take more than 1 million doses of treatment, according to [Dr. James Vincent Lawler (born 1969)]. “Scaling to a million doses of antibody product is a heavy lift to do in a few months,” he says. “We don’t have scaling capacity for therapeutics or prophylaxis in that time frame. In two years, we could get to that point.”

Despite those obstacles, medical researchers involved in the Darpa program say they are ready to fire up sophisticated tools for cellular screening and imaging that have been boosted in recent years by advances in machine learning and pattern recognition. [AbCellera Biologics Inc.]’s machine is trained to look through millions of images to find the perfect one of an antibody binding to the surface of the virus.

At Vanderbilt University’s School of Medicine, Robert Carnahan is also waiting for the blood from that first US patient sample to run through Vanderbilt’s own antibody screening technology. Carnahan and his colleagues at the Vanderbilt Vaccine Center used their method last year to find new antibodies against the Zika virus. Their initial test resulted in 800 antibodies that were narrowed down to 20 for animal testing, and finally one that stopped the virus from spreading. That entire process only took 78 days, Carnahan said.

“We need the most potent antibodies,” Carnahan said. “That requires a lot of work. Most of the work in our lab during the Zika trial was to take a small subset into these more detailed studies. In the midst of a pandemic, you don’t have that luxury.”

Carnahan said he expects to receive the US coronavirus blood sample any day now. Given the lack of US patients, his colleagues are also trying to get them from infected patients living outside of China. But acquiring the samples requires working directly with hospital administrators and public health officials in each country, because no international body is yet coordinating a sharing program.

“Everyone’s anxious,” Carnahan said about the researchers on his team at Vanderbilt. “When the human samples become available, things will progress quickly. And it’s probably OK from a safety perspective that these samples aren’t flying all around the country.”

When we interviewed Clarkson University alumna Amy Jenkins ' 02 (chemistry and biomolecular science) in spring 2020, she was working on an antibody therapeutic that acts as a “temporary vaccine” to prevent infection in individuals exposed to COVID-19. The antibody, which would create an immunity that lasts for several months, was still in the production stage then.

Jenkins is a program manager in the Biological Technologies Office of the Defense Advanced Research Projects Agency (DARPA), a research and development agency of the U.S. Department of Defense. There she manages three programs focusing on medical countermeasures -- both vaccines and therapeutics -- and how to develop and manufacture them faster to combat infectious disease threats.

We recently caught up again with Amy.

What's the latest on the antibody therapeutic you were working on in spring 2020? Did it go into use?

• Yes. We're very excited to report that two of the products from the portfolio that I manage are now either in late-stage clinical trials or have emergency use authorization (EUA) and are being utilized. These were the first leads that came out of this program and I think are on a record development time.

• The first is bamlanivimab from Eli Lilly/AbCellera. That antibody, as it stands right now, has an indication for treating patients who are very early in their course of COVID disease. So, while the use of monoclonal antibodies can prevent disease -- an application that we are absolutely interested in within the Department of Defense -- Eli Lilly entered into those studies to see if they could use it to treat COVID patients and obtained an emergency use authorization for it. It is now being distributed and used around the country to prevent people who are infected and have symptoms, from progressing to severe disease and needing to be put into the hospital.

• The second product, AZD7442, is a combination product. This monoclonal antibody cocktail -- two antibodies being used in one product -- is in late-stage clinical trials with AstraZeneca. This antibody was fully discovered, characterized and developed as part of DARPA's P3 (Pandemic Prevention Platform) program and went on to additional U.S. Government funding to do the late-stage clinical trials. They are currently in a phase-three clinical study with two arms.

• The first takes healthy people and sees if this can act as a preventative -- what we call pre-exposure prophylaxis. You're walking around, you know you haven't been exposed to COVID and you try to prevent that -- similar to a vaccine.

• The second is a clinical trial in a post-exposure prophylaxis setting. So, you may not be symptomatic, but you know you've been exposed to it, you could enroll in this trial. It's looking to see why people do not then become symptomatic with COVID disease and preventing disease in that setting where people know they've been exposed.

What's your role in these two products?

• The companies and academic groups we work with – we call them performers - did all this incredible work. Granted, I was there alongside them on the phone many times, but they do the hard work of actually finding the antibodies. But what we do as program managers is to envision what we think is needed -- establishing if we were to ever encounter this type of situation, how would we solve this problem?

• We try to envision the types of technology investments that need to be made to make it a reality. And that's what I've been managing. Investing in those. Pushing these groups. Keeping them focused.  Having many technical calls to make sure that they're making the progress we anticipate. And if they're not making the progress, we brainstorm on what we can do to fix it.

• And then also on the much less exciting, but absolutely necessary side: ensuring that we're doing everything on the up-and-up from a U.S. Government taxpayers' dollars perspective.

Are you working on any new projects?  

• I am very excited that we have recently been able to launch a follow-on program. The aim of the NOW (Nucleic acids On-demand Worldwide) program is to actually make the capability to manufacture vaccines and nucleic acid-based countermeasures -- think the Moderna mRNA vaccine -- in a distributed setting.

• So, rather than having to manufacture things in one large building in one place in the country and then ship the vaccines around the country, imagine a situation where you could have a fairly small manufacturing device -- think tractor-trailer-sized or half-of-a-tractor-trailer-sized devices or room. And you could have this on-site device that essentially makes thousands of antibody doses every couple of days.

• When we devised the program, we were largely thinking about the Ebola crisis in both West Africa and in the Democratic Republic of the Congo, and how useful it would be to be able to have on-site manufacturing in some of these far-forward remote settings. But I think even in the context of the current COVID response, if we didn't have to ship and we didn't have all the logistics and distribution that comes along with centralized manufacturing, and we could manufacture things where we need them, it might relieve some of the pressure on the system.

Anything else?

• DARPA is always very interested in looking at high-risk-high-reward technologies. Another program that I manage is called the PREPARE (PReemptive Expression of Protective Alleles and Response Elements) program. It's a very high-risk, very early-stage R&D effort to develop a whole new modality for fighting infectious diseases and viruses using the newly emerging CRISPR-Cas technology.

• These are enzymes that can very specifically cut DNA, and there have been newly discovered versions of this that are enzymes that can very specifically cut RNA. The thought was if you have an enzyme that can very specifically cut an RNA, could we design it to very specifically cut the RNA of, for example, Coronavirus or influenza virus, and essentially shred that virus up before it makes us sick?

• This is a very early R&D stage program. We're just doing lab-based type experiments right now, but it has promise in the early stages that you could use these newly emerging modalities for fighting infectious diseases as well.

Did Clarkson play a role in the success you have today?

• Absolutely. It really set me up for success in graduate school. I came to Clarkson as a first-generation college student. I didn't even know how to get a Ph.D. I had professors and advisors at Clarkson that helped walk me through that process. I'd attribute Clarkson 100 percent as laying the foundation for my success.

• I was able to move between chemistry and biomolecular science and had daily conversations with professors and advisors about my interests. They helped me think about taking classes like medical microbiology and classes that I think traditional chemistry majors don't take.

• It allowed me to get a very interdisciplinary background. That's one reason why DARPA's so successful -- we bring together people of such varying backgrounds to solve problems and I think it helps when you have that varying background.

• Professors Phil Christiansen and Jim Peploski were really instrumental in helping me prepare for thinking critically as part of a Ph.D. program. They said, "You're smart, use your brain, and think about it. You'll figure it out. That's what graduate students do." And I used what they told me many times. Use rational thinking and that's your job as a graduate student. I very much accredit them with providing me with that advice.

[...]

The blood of people who have recovered from COVID-19 may be the world’s most sought-after substance right now. It contains a stockpile of antibodies made by immune cells that have successfully mounted an attack on the invading virus, SARS-CoV-2. While multiple efforts are focusing on repurposing existing drugs, like remdesivir or chloroquine, to fight this new virus, many scientists think that the fastest route to novel therapies specifically designed to treat the infection could come by harvesting those antibodies.

These antibody-based therapies could take many forms. The simplest, and the only that is already being tested in people with COVID-19, is convalescent plasma, the antibody-rich portion of blood donated from someone who recovered from the disease. At the other end of the spectrum, companies are meticulously analyzing plasma from recovered humans or immunized animals to select the very best antibodies, which they can use to manufacture traditional monoclonal antibody therapies. These approaches, and others in between, are barreling toward the clinic at a pandemic pace.

The antibody-based therapy that could reach people with COVID-19 the fastest is convalescent plasma, the clear, yellowish, protein-filled portion of the blood collected from people who have recently recovered from an infection. Potential donors must wait at least 14 days for their symptoms of COVID-19 to clear and then must test negative for the virus and positive for antibodies for SARS-CoV-2 before donating their plasma.

“It’s an idea that goes all the way back to the Spanish flu of 1918,” says Warner Greene, a virologist at the Gladstone Institute of Virology and Immunology. It’s been used with varying degrees of success for many infectious diseases, including severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and Ebola virus disease. “It is not a cure,” Greene says. “It just buys you enough time to make your own antibodies.” And that could be particularly important for older people, whose immune systems don’t mount as vigorous of an immune response.

AN ANTIBODY ARMAMENTARIUM

Companies are rushing to discover antibody-based therapies for COVID-19. This is a select list of programs.

• Developer     /      Technology  /  Clinical trial start date
• American Red Cross and Mayo Clinic     /     Convalescent plasma / April 2020
• Regeneron Pharmaceuticals     /     Monoclonal antibody / June 2020
• AbCellera Biologics and Eli Lilly and Company     /      Monoclonal antibody | July 2020
• Vir Biotechnology     /     Monoclonal antibody | Between July and September 2020
• SAB Biotherapeutics     /     Hyperimmune therapy | Summer 2020
• Emergent BioSolutions     /     Hyperimmune therapy | September 2020
• GigaGen     /     Biomanufactured polyclonal antibodies | 2021
• CSL Behring and Takeda Pharmaceutical     /     Hyperimmune therapy | Summer 2020
• Grifols     /     Hyperimmune therapy | Unknown
• Vanderbilt Vaccine Center     /     Monoclonal antibody | Unknown

On March 27, a team of researchers at the Shenzhen Third People’s Hospital in China published a tiny observational study showing that five people with COVID-19 who received convalescent plasma improved (JAMA, J. Am. Med. Assoc. 2020, DOI: 10.1001/jama.2020.4783). Hospitals in Houston and New York City began providing convalescent plasma to people with COVID-19 the next day.

A few days later, on April 3, the US Food and Drug Administration announced a new, coordinated national effort to streamline access to convalescent plasma. The Mayo Clinic is the contact point for donors and for doctors requesting convalescent plasma, and the American Red Cross is collecting and distributing the plasma. A number of hospitals and universities in the US are planning clinical trials to assess the technique’s effectiveness.

“There will be anecdotal data from very ill patients who receive convalescent plasma over the next few weeks that may provide hints about efficacy,” says Jeffrey Henderson, an infectious disease biochemist at Washington University in St. Louis. “It is also possible that the disease will be too far advanced in many of these patients for plasma to be very helpful. There are many unknowns about COVID-19. We are gaining knowledge in a rapid, but piecemeal, manner right now.”

Other groups are collecting convalescent plasma as the base ingredient for a refined product that companies call hyperimmune globulin, in which the antibody fractions of plasma donations are isolated and pooled into a concentrated therapy. “It is much more potent than convalescent plasma,” says Christopher Morabito, head of R&D for Takeda Pharmaceutical’s Plasma-Derived Therapies Business Unit.

Takeda and CSL Behring, two companies that control about half the market for plasma-derived therapies, and four smaller companies formed an alliance at the beginning of April to begin collecting convalescent plasma to make a single, unbranded hyperimmune therapy. Emergent BioSolutions, Grifols, and SAB Biotherapeutics are all developing their own hyperimmune therapies for COVID-19 with support from the US Biomedical Advanced Research and Development Authority.

CSL, Emergent, Grifols, and Takeda all sell approved hyperimmune therapies intended to treat immunodeficiency diseases or specific pathogen infections, like anthrax and rabies, and all are banking on expedited clinical trials and regulatory reviews of their COVID-19 treatments. Morabito says Takeda plans to skip safety studies in humans and smaller studies to gauge efficacy and jump right into a Phase III trial this summer. Emergent, meanwhile, is aiming to start a Phase II trial in September, if the company can start manufacturing this summer, says Laura Saward, head of the Antibody Therapeutics Business Unit at Emergent. “The overall timeline is really dependent on getting sufficient sources of plasma,” she adds.

Although convalescent plasma can be deployed to help people with COVID-19 more quickly than hyperimmune therapy, the concentration of antibodies in the plasma that target SARS-CoV-2, and thus the plasma’s potency, will vary from donor to donor. Saward says that hyperimmune therapies, which pool antibodies from many donors, will be designed to have more consistent antibody levels and will hopefully work more predictably.

Companies say it is too soon to know how many patients can be treated from one plasma donation, but it is likely no more than a few, at best. Emergent is hoping to avoid potential delays in plasma collection by also producing hyperimmune globulins in horses vaccinated with whole or partial bits of SARS-CoV-2. SAB takes this concept a step further, fully relying on its herd of genetically engineered cattle in Sioux Falls, South Dakota, as the source of its experimental hyperimmune therapy for COVID-19, which it expects will be ready for clinical testing this summer.

Others hope to avoid any supply limitations from donors—whether human, equine, or bovine. David Johnson, CEO of GigaGen, calls the hyperimmune approach “old school.” Hyperimmune therapies are one kind of polyclonal antibody therapy, in which many different antibodies targeting a virus are produced by many different B cells. GigaGen specializes in polyclonal antibody therapies that can be manufactured at scale in bioreactors. The start-up will collect blood from about 50 to 100 people that have recovered from COVID-19, find B cells that make antibodies for SARS-CoV-2, and then copy the genes from those B cells into genetically modified cell lines that crank out these virus-targeting antibodies in bioreactors.

GigaGen’s polyclonal antibody approach is comparable to traditional monoclonal antibody production, except instead of mass production of a single antibody, GigaGen’s product would likely contain thousands of different antibodies. It’s like “re-creating the entire immune system” in a drug, Johnson says. He hopes to begin manufacturing in July and start clinical trials in early 2021. The therapeutic and manufacturing strategy is unproven, however, and its COVID-19 program could be the start-up’s first therapy tested in humans.

But convalescent plasma is useful only if there are people around who have recovered. Furthermore, scientists say that our immune system often doesn’t make its best antibodies until a couple of weeks after recovery. Amid a budding pandemic, waiting a month or more for the first samples seems too slow.

So scientists are trying to sift through the many antibodies produced by our immune cells to identify the most effective ones—the so-called neutralizing antibodies, which bind to a pathogen and keep it from infecting cells. Some combination of those in theory could be turned into a drug. And researchers already have experience identifying neutralizing antibodies from similar coronaviruses—the ones that cause SARS and MERS.

Indeed, when SARS-CoV-2 hit, some companies first turned to these SARS and MERS neutralizing antibodies. Vir Biotechnology began screening SARS and MERS antibodies in late January, and by mid-February, it found two that neutralized SARS-CoV-2. Vir has since struck partnerships to bring those to patients: a pact with WuXi Biologics and Biogen will prepare for manufacturing those antibodies, while a deal with Xencor centers on technology to make the antibodies circulate in the bloodstream longer. In April, GlaxoSmithKline made a $250 million investment in Vir and agreed to help speed up the development of Vir’s two antibodies. Vir expects clinical trials could begin this summer, as soon as July.

The rapidity of the discovery, dealmaking, and translation to the clinic highlights the urgency companies are feeling during the pandemic. And although no SARS therapy has ever been approved, Vir’s speed can be partly attributed to the fact that it had several SARS antibodies on deck.

But some scientists doubt that these old antibodies will be useful for treating COVID-19.

“I have yet to see a drug that can be used against two viruses and be efficacious,” says Christos Kyratsous, head of infectious disease research at Regeneron Pharmaceuticals. It’s possible to design drugs that target multiple coronaviruses, he says, “but the broader you get, the harder it is to discover something that is important.”

That’s why most groups are focusing on neutralizing antibodies that are designed specifically for SARS-CoV-2. Industry and academic labs are taking a variety of approaches to discover monoclonal antibodies or concoct cocktails of these antibodies to treat COVID-19. Regeneron has emerged as a leader in the monoclonal antibody race by taking a somewhat unique approach. The company uses mice that are genetically engineered to produce human antibodies when exposed to a virus. It’s the same approach Regeneron used to discover three monoclonal antibodies for the Ebola virus during the 2014 outbreak.

Those antibodies were used in an experimental treatment called REGN-EB3 during the Ebola outbreak in the Democratic Republic of the Congo in 2018 and 2019. The trial was stopped early because of overwhelming evidence that Regeneron’s therapy saved significantly more lives than ZMapp, another trio of monoclonal antibodies. Regeneron plans to submit REGN-EB3 to the FDA for review this year.

Motivated by its success with Ebola, Regeneron began a monoclonal antibody discovery program for SARS-CoV-2 soon after the virus’s genome was posted online in mid-January. Regeneron had previously worked on two antibodies for the MERS coronavirus in 2016. Like other coronaviruses, the one that causes MERS binds to the surface of human cells using its spike protein. Since some antibodies that target the spike proteins of the viruses that cause SARS and MERS can prevent the viruses from infecting cells, Kyratsous’s team decided to look for antibodies that bind the SARS-CoV-2 spike protein.

In early February, Regeneron scientists began immunizing its genetically engineered mice with the SARS-CoV-2 spike protein, produced with the genetic instructions in the virus’s genome. After the mice mounted a strong antibody response to the spike protein, the team began isolating B cells from the mice and screening them to find the most potent mouse-produced antibodies against SARS-CoV-2. “We screened 3,000 or 4,000 and ended up with a few hundred that block coronavirus entry into cells,” Kyratsous says. In late March, the team began winnowing that number down to find the top two that bind to nonoverlapping sites of the spike protein. The company will also isolate antibodies in human convalescent plasma to compare them to the best mouse antibodies.

While that work is ongoing, other scientists at Regeneron are already preparing the cell lines that will ultimately be used to manufacture its top two antibodies. The parallel work is necessary if the biotech firm is to meet its ambitious timeline of having its first batch of antibodies ready for clinical testing in June.

Kyratsous says that Regeneron is looking to study its top antibodies in mouse and monkey models of COVID-19 in late May or early June, meaning that these animal studies will likely start soon before, or at the same time as, a clinical trial. Regeneron’s urgency to get its antibodies tested in humans will reflect the severity of the pandemic at that time, Kyratsous says. “It will be a risk-benefit calculation.”

The COVID-19 pandemic is testing the limits of what rapid drug development means. Monoclonal antibody programs initiated in January or February that begin testing this summer will set records for their speed. But even with that speed, manufacturing monoclonal antibodies and scaling up to larger batches is laborious and time consuming.

Long before this pandemic began, a division of the US Department of Defense had been working with academic and industry partners to develop a plan to go from pathogen identification to human testing of a new therapy in just 60 days.

In late 2017, the Defense Advanced Research Projects Agency (DARPA) launched its 4-year Pandemic Prevention Platform (P3) program. Its mission was “to halt the spread of any infectious disease outbreak before it can escalate into a pandemic.”

Four separate teams at AbCellera Biologics, Duke University, MedImmune, and Vanderbilt University were chosen to develop tools and strategies to complete two tasks: first, rapidly identify antibodies that can neutralize a new pathogen; and second, encode the antibody in DNA or messenger RNA (mRNA) for injection into a human, where that nucleic acid code will transform an individual’s cells into a personal drug factory. DARPA P3 program manager Amy Jenkins anticipates that these nucleic acid therapies can be manufactured much more quickly than traditional antibodies.

Each year, the program has researchers put their technological developments to the test with a mock challenge. In January 2019, the groups were given convalescent plasma from survivors of the Zika virus. This January, Jenkins was visiting one of the P3 teams at the Vanderbilt Vaccine Center just as it was gearing up for a new challenge. After the first coronavirus case hit the US a few days later, the team decided to skip the trial run and try to make an antibody therapy for real.

James Crowe and Robert Carnahan, the director and associate director of the Vanderbilt Vaccine Center, respectively, began feverishly reaching out to health-care providers and local health authorities to pin down some of the earliest cases of COVID-19 in North America to identify recovering patients who might donate their plasma. The Vanderbilt team eventually got four samples that it has used to identify about 1,500 antibodies that target SARS-CoV-2. Now the researchers are working with academic collaborators to determine which of those antibodies are best at neutralizing the virus.

AbCellera, another P3 group, received its first convalescent plasma sample on Feb. 25. Within 8 days, the start-up had identified 500 unique antibodies that bind the SARS-CoV-2 spike protein. AbCellera is now screening them with its partners at the National Institutes of Health to see which ones are the best at neutralizing the virus. The pharma firm Eli Lilly and Company has committed to manufacturing the best ones for clinical trials, which may start by late July.

Jenkins says that the P3 groups will stick to making traditional antibody therapies during this pandemic rather than encoding them in DNA or mRNA. “These technologies are still fairly risky,” she says.

But even traditional monoclonal antibodies are relatively unproven as infectious disease treatments. The drugs are typically expensive to produce, and although several experimental monoclonal antibodies have been made, only one—MedImmune’s palivizumab, which prevents respiratory syncytial virus (RSV) infections in children—has demonstrated it can prevent infectious disease in humans.

• CORRECTION :     This article was updated on April 8, 2020, to note that GigaGen collects blood, not convalescent plasma, as the basis of its therapy because convalescent plasma does not contain B cells.

A Pentagon agency is working to produce an antibody treatment to combat the novel coronavirus until a vaccine is ready.

The Defense Advanced Research Projects Agency (DARPA), a research and funding branch of the Defense Department known for its out-of-the-box innovations, aims to "make pivotal investments in breakthrough technologies for national security." Its inventions include the internet, Siri, GPS, videoconferencing and even self-driving cars. 

Now, DARPA is racing against time as experts warn of a likely second wave of the coronavirus this fall.

Dr. Amy Jenkins leads DARPA's Pandemic Prevention Platform (P3). The program, which launched in 2018, works with outside researchers to develop a quick response to emerging infectious diseases with a goal of delivering medical countermeasures in 60 days. P3 is currently working with two universities, Duke and Vanderbilt, and two pharmaceutical companies, AbCellera and AstraZeneca, on a COVID-19 response.

Their primary focus is to create an antibody therapeutic, which Dr. Jenkins called a kind of "temporary vaccine" to prevent infection if individuals are exposed to COVID-19. Unlike a regular vaccine, which creates permanent immunity, this therapy would create immunity for several months. The intention is to utilize this treatment as a bridge until a vaccine is developed. The antibody therapeutic would be immediately effective because the body starts producing antibodies within hours, as opposed to a traditional vaccine, which can take weeks.

"In vaccines, you're literally teaching the body to fish, so to speak. You're teaching it how to make the antibodies that would be protective against the pathogen of interest," said Dr. Robert Carnahan, Associate Director of the Vanderbilt Vaccine Center, one of the teams working with DARPA on this effort. "We're not doing that here. We're not teaching the body, what we're doing is literally jumping to the end of that, and giving them the final product which is the antibody itself. …We're literally giving them the fish."

Dr. Jenkins stressed that this would not replace a vaccine, but would be meant as a firebreak.

"We're trying to put the ring around the people who are the most affected by this to stop the potential future spread of it," Dr. Jenkins told CBS News. They intend for this therapeutic to be administered in a targeted manner — to give temporary protection to front-line health care workers and first responders in hot spots that may develop in specific communities.

Using the blood from several recovered coronavirus patients, including Washington One, the first known infected patient in the United States, the P3 researchers have been searching through thousands of antibodies for the top three most potent ones that have the greatest capability to fight the coronavirus. Dr. Jenkins likened this to "finding a needle in a haystack."  

Up until about five years ago, that process alone could have taken several years, but DARPA has invested in technology that enabled researchers to find those antibodies in a matter of weeks, according to Dr. Jenkins. 

Once those antibodies are identified, there are two paths forward in producing this "firebreak" treatment. The first is the more traditional method — to manufacture these antibodies in large quantities for widespread distribution. Dr. Jenkins said that process will begin within the next two weeks.

The pharmaceutical companies AbCellera, in partnership with Eli Lilly, and AstraZeneca, will grow the antibodies in giant steel tanks that resemble beer fermenters, called bioreactors. The manufactured material would then be purified, tested and injected into patients for temporary immunization. Traditionally, the manufacturing process can take several years, but DARPA is aiming for a much shorter turnaround in this case.

"We want to trim that timeline from two-to-five years down to 60 days. And people say that's impossible. You can't do it. Well, that's what we're here to do," said Dr. Jenkins. "We're meant to be pushing that scientific and technological bar to the point that we potentially can get there." She adds that even if DARPA accomplishes this task in 90 to 120 days, it will still revolutionize this field.

DARPA has decided not to just focus on these bioreactor-grown antibodies, but to push the envelope even further by investing in technology that enables them to turn patients' own bodies into bioreactors.

Dr. Carnahan told CBS News that in this second method, researchers will extract the antibodies' genetic code, which they will then replicate and inject into patients so their bodies produce new antibodies. According to Dr. Carnahan, "What's immunized in that case is the blueprint for the antibody, and then the cells take up the blueprint and they're able to produce the antibodies themselves."

The P3 teams are working on the bioreactor-based and the gene-encoded antibody approaches simultaneously. They plan to begin clinical trials by this summer, and to deploy the treatments by this fall or early 2021.

Dr. Jenkins called this technology a "game-changer" in how we can respond to future pandemics or infectious disease threats. 

"We had a leg up this time, to be honest," said Dr. Jenkins. "We had a little bit of a leg up in that this is quite similar to SARS, at least from a structural standpoint. It looks a lot like SARS. Its sequence is somewhat similar to SARS and that did allow us to move a little bit faster on some of the things that we needed to get this in place. But the goal of our program here actually is to be able to respond this quickly, no matter what the threat."

[...]

Amy Jenkins is Program Manager at the Defense Advanced Research Projects Agency (DARPA). Her research interests include the development of platforms for combatting infectious disease threats as well as novel manufacturing methods to enable rapid response. Before to joining DARPA, Dr. Jenkins was a Senior Scientist at Gryphon Schafer where she contributed to development of programs targeting infectious disease threats within the Biological Technologies Office. Previously, Dr. Jenkins studied the virulence factors of, and antibodies targeting, multi‐drug resistant bacterial pathogens at MedImmune. She served as a National Research Council Postdoctoral Fellow at the United State Army Medical Research Institute of Infectious Diseases where she studied virulence mechanisms of biodefense pathogens. She received her PhD in chemistry and chemical biology from Cornell University. 

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DISRUPTIVE TECHNOLOGIES AND CONVERGENT INNOVATIONS

Gustavo Mahler, managing partner at Dynamk Capital, began the final session by offering a perspective from an investor in start-up life science industrials, which he described as companies that drive innovation by developing tools and services that increase yields and productivity and reduce costs of discovery, development, and manufacturing of biopharmaceuticals. He provided his view on innovations in biopharmaceutical manufacturing that could appear in FDA submissions in the next 5–10 years. He said that start-ups are innovating in cell-line development and are focused on high-yield systems that use alternative hosts, synthetic biology, and high-throughput selection of high-producing cells. Companies are also working on cell-free systems. Single-use bioreactors are an important innovation that has recently emerged, and companies are refining this technology by incorporating process intensification methods. Given the increase in titers upstream, he said, downstream processing is an area that has major challenges and that companies are developing alternate cell separation methods based on physical principles, continuous chromatography, membrane-based chromatography, and single-use concentration equipment to address the challenges. Regarding the final production stages, Mahler noted that alternate formulation and active-pharmaceutical-ingredient fill and storage methods are being developed to achieve high concentrations, temperature stability, and better protection of the ingredients after formulation. As a final area of innovation, he noted the creation of new software applications to design and control processes better and the development of multiple options for in-process control technologies and high-throughput analytical technologies, such as inline or offline metabolite monitoring or analysis, fast-separation methods to replace traditional methods, and cell-based in vivo analysis using microfluidic devices. He concluded that funding partners that understand market dynamics and commercialization of new products are crucial for accelerating innovation in bioprocessing but that it is important to remember that new products take several years to enter the market and will probably be adopted first for clinical development of biopharmaceuticals.

Amy Jenkins, program manager at the Defense Advanced Research Projects Agency (DARPA), discussed novel manufacturing approaches to enable rapid responses. She noted that DARPA invests in technologies that are in early developmental stages and will not be ready for commercial applications for many years, possibly decades. One area in which DARPA has great interest is the manufacture of vaccines within days of sequencing the genome of a pathogen. The goal is to have a vaccine approved for use within weeks to confront disease outbreaks and pandemics. Her group is specifically focused on manufacture of nucleic acids. Because nucleic acids might be used as therapeutics as opposed to vaccines, it is not clear where these products will be regulated, and thus this topic should be of interest to the committee that is hosting this workshop. At first, the focus of her group was on finding antibodies, creating nucleic acid constructs, and delivering them to patients, but the group soon recognized that manufacture of high-quality nucleic acids was going to be a bottleneck, given all the challenges associated with cell systems. So, it recently launched a program whose goal is to develop a cell-free system for production of nucleic acids. She noted that challenges for the upstream process will be polymer length, the need for an error-free synthesis, and ensuring simplified starting materials, and challenges for the downstream process will be creating automated production and integrated quality control and product identity assessment. The hope, she said, is that one day there will be an end-to-end system that can manufacture high-quality nucleic acids that can eventually be miniaturized so that the technology is deployable. In response to a question, she noted that the technology envisioned will not be scalable to produce large quantities but that the technology itself can be deployed to many locations. She acknowledged that the regulatory hurdles could entail trying to approve a novel technology and a novel product, such as a linear-DNA vaccine or therapeutic.

• Suggested Citation:"Barriers to Innovations in Pharmaceutical Manufacturing: Proceedings of a Workshop - in Brief." National Academies of Sciences, Engineering, and Medicine. 2020. Barriers to Innovations in Pharmaceutical Manufacturing: Proceedings of a Workshop–in Brief. Washington, DC: The National Academies Press. doi: 10.17226/25907.×

Noubar Afeyan, chief executive officer and founder of Flagship Pioneering, discussed innovations in life-science platforms and some challenges. He began by describing three novel drug modalities that modulate the gut microbiome. The first encapsulates a consortium of bacteria that is designed to restructure the microbiome and modulate disease pathways and is formulated for oral delivery in accordance with good manufacturing practices (GMPs). He listed several manufacturing and quality-control issues that will need to be solved and emphasized the challenges of producing anaerobic microorganisms in spore form and establishing the identity, purity, potency, and safety of a product that is a mixture of microorganisms. The second novel drug modality involves monoclonal microbials that are isolated, fermented, and purified in ways that are similar to those for the manufacture of other pharmaceuticals, although advances beyond current practices were required to produce a specific strain in large quantities and formulate it for oral delivery. The third example was the manufacture of glycans (complex oligosaccharides) to modulate the metabolic profile of the microbiome. For the glycans, a manufacturing process similar to that for small molecules was developed. The process produces many diverse glycans by using small-batch synthesis, integrates multiple analytical methods for structural characterization, and is scalable and transferable.

Afeyan next highlighted two innovations in novel “delivery” vehicles. He first described a new platform that uses anelloviruses for gene delivery. Technical challenges include cell and viral genome engineering, efficient capsid assembly, process design and scale up, supply-chain optimization, and product design for specific tissue targets. The second example highlighted the development of customized exosomes as targeted delivery systems for proteins, RNA, or DNA. He noted that successful industrialization of exosome manufacturing required development of proprietary centrifuge-free purification and proprietary analytical methods to confirm product quality, potency, and consistency. He added that intensified continuous manufacturing is being investigated as the next-generation platform to improve productivity and efficiency and reduce the equipment footprint.

Afeyan concluded his presentation by describing three innovations in cellular therapy. The first involves the use of a novel biocompatible matrix to protect engineered human cells from immune attack and fibrosis. The innovative and scalable automated encapsulation system that was pioneered provides both protection and durability that are commonly lacking in the delivery of cellular therapies. The second innovation involves externally primed T cells with slow-release potent immune agonists to target tumors. The manufacturing process is both scalable and cost-efficient. The third innovation involves the engineering of enucleated red blood cells for use in several therapeutic categories. Manufacturing challenges include substantially improving volumetric productivity, lowering operating costs, and securing raw materials that can ensure safety and supply continuity for the pipeline. In closing, he said that each innovation described presents new challenges but that all indicate how far biological therapeutics have come over the last 3 decades.

Discussion

Todd Przybycien, a professor in the Howard P. Isermann Department of Chemical and Biological Engineering at Rensselaer Polytechnic Institute, moderated a panel discussion with the speakers and the workshop audience. Most of the discussion centered on various aspects of advancing innovations. The most important criteria for success, Mahler said, are that the technology can meet GMPs, that the supply chain is reliable, that the developer is financially sound, and that the data show that the technology works. He added that including people who have quality-assurance experience early in the development process is critical. To advance novel products, such as microbiome therapeutics, Afeyan noted the importance of working closely with FDA to identify and address issues associated with regulation. Mahler agreed and added that a challenge is the validation procedure; a company will need to establish clear criteria and provide a good rationale for the validation approach for novel systems. The one who makes the first submission will suffer the pain of discovering what it takes to validate the system, he said. In response to a question on how to assess viable investment opportunities, Mahler said that technologies that solve problems or enable someone to take a product to market are clear choices and that technologies that could provide substantial advantages in reducing costs or complexity are also attractive. Przybycien asked the panelists whether a database of common regulatory pitfalls for various types of innovations would be helpful. Mahler and Jenkins agreed that such a database would be helpful for driving innovation and emphasized the importance of clear FDA guidance on validating new technologies. As a final follow-on question, the panelists were asked whether there is a “playbook” that provides regulatory guidance to innovators. Afeyan was not convinced that such a playbook would be useful for innovative technologies and cautioned that knowing what worked or did not work in the past might not apply today, especially with regard to biologics. Mahler countered, however, that there are several basic rules to consider: understand the regulatory implications of the technology being developed, consider how the product will be commercialized and its quality ensured, understand the supply chain and determine who will be the suppliers, and do not underestimate the investment costs in either time or money.

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• Name :    Amy L Jenkins   (Amy Lynn Jenkins, Amy Lynn Haas)

• BIRTHDATE :   6/9/1979 (44yrs)

• LOCATION :   North Potomac, MD

• Relatives & Associates  :   Amy has 5 relatives and 5 associates.

  • • Tyler R Haas  /   Age 20s  /   Massena, NY

    • Neil E Jenkins  /   Age 40s  /   North Potomac, MD

    • Wayne A Haas  /   Age 60s  /   Massena, NY

    • Noah James Jenkins  /   Age 20s  /   North Potomac, MD

    • Ryan J Haas  /   Age 30s  /   Massena, NY