Prognosis for coronavirus vaccines has become almost deaf in recent weeks, but whether or not the first doses of the vaccine arrive this year, some people will continue to get sick. A drug that can prevent people from progressing to such an extent that they need a hospital bed or ventilator can be a bridge to a vaccine, or it can be a lifeline that can give people the confidence to return to normal life, even after vaccines have been developed.
In the search for such a countermeasure, Nobel Prize-winning monoclonal antibodies, biotechnologies developed in the 1
Promising but preliminary data have strengthened the chorus of hope around monoclones from senior health officials.
They are “the real best chance to change the game,” according to Francis C. Collins, director of the National Institutes of Health.
“We’re looking for big effects on disease, not the small side effects we often see in the ordinary development of drugs,” said Janet Woodcock, who is leading the development of therapeutic tools for Operation Warp Speed, the Trump administration’s initiative to provide treatment and vaccines. covid -19, a disease caused by the coronavirus.
One thing is for sure about monoclonal antibodies: If the pandemic continues to rage, it will not be enough. Unlike conventional pills, these are expensive, injectable drugs synthesized by living organisms in specialized reactors, at a biological pace that cannot be rushed. There is a global struggle to find capacity to produce drugs, with companies entering into deals with competitors to increase their production capacity.
Even then, to create enough antibodies to treat all people diagnosed with covid-19 so far, all global monoclonal production capacity will have to be transferred within a year, according to an analysis conducted for The Washington Post by BioProcess Technology Group to the global accounting firm BDO, which advises the pharmaceutical industry. Reactors that produce monoclonal antibodies are now mostly busy producing basic drugs for people with cancer and autoimmune diseases.
“I pray to God that these therapies work,” said Howard Levine, national leader of BDO’s BioProcess Technology Group. “But in the short term, I think there will be a problem in getting enough to treat each individual patient.”
Creating a prescription
When the deadly pneumonia was diagnosed in China in January, scientists at Regeneron Pharmaceuticals knew about the exercise. As with Zika, Ebola, and a close cousin of the new coronavirus, a Middle East respiratory syndrome, the researchers began therapy using the company’s own platform, what their CEO Leonard S. Schleifer calls “magic mice.” These rodents, genetically engineered to have a humanized immune system, can assemble human antibodies that serve as a template for a new drug.
On January 21, a week after the start of research, Christos Kiracus, vice president of research, made an unusual call asking his colleagues to prepare for the production of a drug that does not yet exist.
“It will probably move fast,” he told Hanne Buck, senior vice president of preclinical production, who is developing the initial recipes to turn scientific experiments into a repetitive process. “How fast can you move?”
Buck’s colleague Daniel Van Plue, who oversees industrial operations and product delivery – including a global team of 4,000 people and a massive facility filled with giant tanks connected by steel arteries through pipes – visits Buck that day. Together, they outlined the first deadlines for increasing drug production.
Many of the steps had a natural speed limit – the scientists had to expose the mice to a form of the virus, wait for their immune system to respond, and then study the antibodies. The researchers also tested antibodies from people who had recovered from the virus. They had to test which ones were the most powerful and then engineered hamster ovary cells to produce those antibodies. They will have to feed and nourish these cells for a month – with scientists looking for the laboratory equivalent of Goldilocks.
“You are dealing with a living system. … The amount of oxygen, the food, the way [cells are] excited [in the vat]”Little things can break it,” Van Ple said. “For all intentions and purposes, he has a memory – if you do something bad to him at the beginning of production, it may not turn out so well at the end.”
The scientists tried to move everything else as fast as possible, pretending that there were no dinners or weekends. Regeneron divided his staff into pods in March, so if one person falls ill, he will not take the entire team out for a two-week quarantine.
This meant changing the way people usually worked. Instead of one person owning a project from start to finish, the pods that will come on Monday will do all the science they could, and then hand over their work to the pod that entered on Tuesday, which will continue where have stopped.
After the cocktail, a combination of two antibodies, was selected, Buck’s group began boiling the cells in early April. Typically, her team carefully develops a complete prescription to create a batch of the drug and then passes it on to the Van Ple team, which will bring it to the scale needed to provide clinical trials and, ultimately, to patients.
This is the difference between making dinner for two and making the same dish for a giant banquet, when suddenly what worked on a small scale can go wrong – the vegetables are not heated evenly, the cake does not rise or the sauce does not shrink. Similarly.
But the pandemic meant that Van Ple’s team started just two weeks after Buck’s team, when the recipe they followed was still full of blanks. Bak’s team had to figure out the steps in two weeks and then send him to Van Plew’s team to take him on an industrial scale.
“It was almost like a relay race – you have to stick to the relay and no one refuses,” Buck said.
After the cells grow for about a month, the scientists must release the antibodies. The process takes four days, according to Taylor Houtaling, an associate manager who supplies protective equipment for clean room conditions and uses specialized techniques to purify the drug during 12-hour shifts.
Houghtaling recalled that on the day the first antibody harvest ended, she arrived in the morning and stayed until midnight. During her six years at Regeneron, she had done the same thing many times for other drugs, but no one was more exciting. Many members of the drug teams stayed on the floor tonight to see the first harvest enter a special bag of drugs that can be given to patients.
“At the last stage, we don’t necessarily know how well this treatment will work, but at this point we could make history,” Houtaling said. “The excitement in the room – we were wearing face masks so you couldn’t see anyone’s mouth. But they all shone. “
To make this moment of triumph a viable treatment, ongoing clinical trials will need to show that monoclonal antibodies are safe and effective and determine the best dose. Drugs are being tested on three fronts: to see if they can prevent disease in people who have been exposed to the virus, to help people recover early in the disease, or to treat patients who are hospitalized.
The treatment dose will require much more medication than the preventive dose, so the ability to treat humans will depend largely on what the studies show. Many experts hope that drugs can prevent disease by providing crucial protection for the elderly, whose immune systems may not respond well to vaccines.
The data is starting to leak. Regeneron announced on Tuesday that its drug appears to infect the virus, reduce virus levels and relieve symptoms when given to people recently diagnosed with covid-19 who have not been in the hospital – especially in people whose bodies are not. had a strong immune response.
Eli Lilly announced in September interim “proof of concept” data that his monoclonal antibody showed signs of reduced hospitalizations when given to people in an outpatient setting. Data are preliminary and not yet reviewed, and both studies are ongoing.
To prepare for the drug production on a large scale, Regeneron transferred its remaining products to its plant in Ireland. It recently struck a deal with rival Roche to rapidly increase production.
“This is quite unusual because we give the competitor a lot of our know-how, our technology,” said Schleifer, CEO of Regeneron. “They’ll drive our cars, so to speak.”
With the partnership, companies can produce between 650,000 and 2 million doses per year, or 4 million to 8 million doses for prevention. The United States has ordered $ 450 million worth of drugs, enough for 70,000 to 300,000 treatments, depending on how much of the drug is in each dose. But since the Centers for Disease Control and Prevention predicts 1,500 to 5,000 hospitalized patients a day until the end of October, this supply can be consumed quickly.
This put companies in the unusual position of hoping competitors would succeed and think about how to make an effective drug and increase yields. Eli Lilly initially tested a monoclonal antibody, which could allow the company to produce twice as many drugs as a cocktail approach.
“In terms of production efficiency, generating as much as possible to help as much as possible is simpler and easier if you have an antibody,” said Andrew Adams, vice president of new therapists. modalities in Lilly, which plans to make in at least 1 million doses by the end of the year.
Scientists at California-based Vir Biotechnology are developing an antibody designed to be effective at very low doses, hoping to produce 10 million doses a year.
“Vaccines can be mass-produced for billions of people. The antibodies will be for millions of people, “said Phil Pang, Vir’s chief medical officer.
Many experts believe that although demand will exceed supply, there will be no silver bullet to end the pandemic, but the convergence of modern technology and old-fashioned public health measures. Monoclonal antibodies – potentially from many companies – will begin to make the disease less dangerous. First-generation vaccines will begin to limit the spread of the virus.
“We can’t cure the whole country,” Schleifer said. “But I think if something was there, if you knew that if your wife got sick or your husband got sick, you’d get a shot that would keep you from getting sick – or if you did get sick anyway. [you could be treated], this would change the attitudes of many people. “