By Natalie Eilbert
Medill Reports

When President Donald Trump stood before Americans and called his bout with COVID-19 this fall a “blessing in disguise,” he touted Regeneron as the new pharmaceutical “cure” the world has been desperate for. His doctors at Walter Reed Hospital expedited the experimental antibody treatment he received and combined the antibody cocktail with the antiviral drug, remdesivir, plus a powerful steroid normally reserved for severe cases of COVID-19.

The president has extolled hydroxychloroquine, a prescription drug used to treat malaria and Lupus, and other supposed “cures” to the dismay of most medical professionals. But despite some caveats, REGN-COV2, the antibody cocktail by Regeneron still in clinical trials to which the president was referring, and LY-CoV555, a competing antibody cocktail by Eli Lilly also in clinical trials, shows promise recognized in the science community. And if the FDA approves the clinical trials of either firm’s antibody cocktail, we could have a scalable formula prepared for the next novel virus outbreaks.

Dr. Laszko Takacs, a professor of genetics at the Medical University of Hungary at Debrecen, said that for patients in severe cases, monoclonal antibodies, or mAbs, are expedient drugs that deliver relatively quick relief even if it’s not a “cure.” MAbs are considered immune checkpoint inhibitors, according to Takacs. When the body is sick, immune cells can turn “on” or “off” depending on whether they detect normal or foreign cells in the body. Certain foreign cells as in the case of cancer cells, can skirt past these checkpoints without detection, and that’s where the immune checkpoint inhibitors come into play. They keep the immune system in “on” mode.

James Krellenstein, executive director of PrEP4All, an organization dedicated to HIV medical access that now includes COVID medical leadership, said calling REGN-COV2 a “cure” is inappropriate for a few reasons. First, viral diseases such as COVID-19 move too quickly in too many body types for terms such as “cure” to be relevant. More important, the clinical trial data isn’t strong enough yet to offer certainties about how effective monoclonal antibody therapies are at treating COVID-19.

“From the very limited clinical data we have, we know that there is a dose dependent relationship with viral load reduction but not with clinical endpoints,” Krellenstein said. Trump received a high dose of the drug, which, at clinical trial, is a single eight-gram dose. “So although we saw a greater reduction in viral loads in higher doses versus lower doses, that relationship didn’t hold for clinical endpoints, like time-to-symptom alleviation.”

Regeneron went with a higher dose in clinical trials so as not to “leave any potential treatment benefits on the table,” said Regeneron co-founder, president and chief science officer Dr. George D. Yancopoulos at a REGN-COV2 Antibody Cocktail Program Update webcast in late September.

Moreover, the problem lies less with “cures” or clinical efficacy and more with development and production. Beyond the question of clinical trials is the more urgent matter: Who will be able to get the drug, and when?

Regeneron products are engineered at the milligram scale. These cocktails are challenging to manufacture because mAbs have biological origins rather than being drugs synthesized from chemicals, as is the case for ibuprofen and NSAIDs. In the case of mAbs, scientists commonly express antibodies from the cell line of Chinese hamster ovaries (CHO), because their mutations allow them to reproduce indefinitely in a culture media such as a test tube, flask or bioreactor, according to Krellenstein.

“The problem with CHO is that, being able to grow mammalian cells is delicate, because you need to grow them outside of a body,” said Dr. Jacob Glanville. Glanville is the CEO of Distributed Bio, a company that does contract research for pharmaceutical companies such as Pfizer and Boehringer Ingelheim as well as multiple arms of the US military.

“So you need to have these big vats, you need to manage the temperature, the nutrients, the oxygen levels, the CO2 levels and you need to have a whole bunch of safety protocols around it because mammalian viruses could infect the cells and then also infect the people who receive it,” Glanville said.

But extracting and using these cells for cloning purposes isn’t the problem; regulatory control is part of the process of any type of drug. Rather, according to Krellenstein, it’s a matter of equipment shortage for the genetic engineering process itself. Not only is there a dearth in bioreactors, but also the supplemental equipment to process and purify what becomes the eventual drug.

“If we want to even come close to meeting global demand for [COVID therapeutics], we’ll probably have to make as much monoclonal antibody in the next couple months as the entire world made last year,” Krellenstein said.

If all goes well—if it doesn’t cost an arm and a leg, is abundant and, most important, works—it “ends the medical crisis,” Glanville said, the same way we have done with tuberculosis, the flu, HIV, staph infections and the like: by downgrading the dangers in getting sick.

“These [diseases] are not great, but we have medicines for them, which makes them not a crisis. They don’t kill enough people that justifies altering society, for better or for worse. That’s the value of a therapy,” Glanville said.

The advent of antibody therapies could create a viable technology platform for future outbreaks. And what excites Glanville is the potential creation of broadly neutralizing antibodies, or bNAbs. These types of antibodies recognize the “Achilles heel sites” on viruses so that, year to year, the virus cannot mutate. If a viral cell is unable to mutate, it can’t form resistances against treatment.

Krellenstein compared the level of coordination this will take to the Manhattan Project, the cover name for the World War II production of the atom bomb headquartered at Los Alamos and coordinated across the country, from Oak Ridge, Tennessee, to Hanford, Washington. “We know how to do this. It’s just a matter of scaling up the process, and we’re very good at that. We just need to choose to do it.” For Krellenstein, success is dependent on collective contributions rather than an arms race from private firms.

Producing enough of the therapeutics will be a great challenge, whether at a production level or an economic one. “It would be economically impossible to provide this treatment for people who did not present serious [symptoms] of the disease,” Takacs said. But not too serious “mid-level infection is when monoclonals are most effective.”

Glanville thinks there’s a big opportunity to figure out a large-scale manufacture and to sort out an alternative price model for everyone to have access to these drugs. Distribution Bio, Glanville’s company, is finding the right antibodies that are not only capable of solving the current crisis, but anticipatory in neutralizing future versions of this crisis.

Krellenstein invoked the Manhattan Project reference with a daunting but hopeful prospect.

“We’re talking about building new factories. We need some of the smartest people in the world figuring out how we are going to be able to make monoclonal antibodies at a scale we have never done before,” Krellenstein said. “We can do this, but it needs coordination, it needs collaboration, it needs leadership.”

Natalie Eilbert is a health, science and environmental reporter at Medill. You can follow her on Twitter at @natalie_eilbert.