At a malaria research conference five years ago in Senegal, scientist Timothy Wells presented an overview of medicines on the horizon, ending with a few slides focused on an outlandish idea.
Wells proposed that monoclonal antibody drugs — a class of high-price medicines that has transformed the treatment of cancer and autoimmune diseases — had a role in preventing malaria, a mosquito-borne disease that kills more than a half-million people each year, mostly children in Africa. Scientifically, it was plausible. Practically speaking, it seemed ludicrous.
“That was the only thing anyone asked me questions about at the end,” said Wells, the chief scientific officer of Medicines for Malaria Venture, a public-private partnership that seeks to develop effective and affordable drugs for malaria. “The principal pushback is that this is going to be too expensive.”
For more than three decades, monoclonal antibodies have been powerful, primarily first-world medicines with thousand-dollar price tags. The laboratory-brewed proteins are produced by living cells grown under controlled conditions in giant vats. The coronavirus pandemic showcased the largely untapped potential for monoclonal antibodies to be leveled against more-commonplace threats such as infectious diseases — if the impetus and money exist.
Monoclonal antibody drugs were the first tailor-made covid-19 treatment out of the gate, highly effective medicines that helped buy time before vaccines could be widely deployed. A preventive monoclonal, Evusheld, gave people who do not respond well to vaccines a high level of protection over months.
“People still tell me it’s crazy, but … Evusheld is a tipping point in the history of infectious disease,” said James E. Crowe Jr., a viral immunologist at Vanderbilt University Medical Center whose work underlies the drug. It took a little more than three weeks for his team to identify coronavirus-blocking antibodies in a blood sample from a person who survived covid-19 and to send those leads off to the drug company AstraZeneca.
Scientists see enormous potential in harnessing antibody drugs against an array of infectious-disease threats — if the costs come down. Multiple promising studies have identified antibody drugs that could prevent malaria, treat a hemorrhagic illness called Lassa fever or block Zika. Monoclonals could be deployed to smother outbreaks, protect people against diseases for which there are not yet vaccines and shield the most vulnerable who are not well-protected when vaccines do exist.
But the pandemic also exposed huge challenges: The drugs can cost thousands of dollars per treatment, are often given by onerous intravenous infusions and can quickly become obsolete as pathogens evolve.
Those realities make optimism about using monoclonals against tropical diseases far from mainstream. Wells said production costs are closely guarded trade secrets but estimates that producing a gram of antibodies for about $50 could be feasible — meaning a dose might be about $5.
That’s not cheap enough. These drugs are still years away from the real world, and some doubt they will ever be feasible outside of limited applications such as protecting those traveling to disease hot spots.
Still, scientists are pushing the envelope, searching for ways to increase the potency of antibodies, decrease the costs of production and challenge the prevailing assumptions about who can benefit from cutting-edge medicine. If they succeed, they could begin to recast how these drugs are used globally.
Peter D. Crompton, the chief of the Malaria Infection Biology and Immunity Section at the National Institutes of Health, has been testing an anti-malaria monoclonal infusion with colleagues in Mali. He says the reflexive response that such drugs are too pricey to be practical reminds him of the debate in the 1990s about whether antiretroviral treatments that had begun to transform HIV in wealthy countries were too costly and complex to be used in Africa.
“That was a lesson to me, that if we, as scientists and researchers, develop highly effective, safe tools, there can be a way forward, once people begin to see that it is effective,” Crompton said. “If we stop and wring our hands about how are we going to afford this, that would be paralyzing.”
Back to the future
Before antibody drugs became powerful and expensive weapons against cancer and autoimmune diseases, they were used to treat infections.
In the late 1890s, scientists began exposing rabbits and horses to “toxins” from pathogens, and then harvesting their serum — the yellowish part of blood that contains antibodies — to treat diseases such as diphtheria and tetanus.
Scientists hadn’t yet unraveled the full complexity of the immune system, but their work laid the foundation for the idea of “passive” immunity. Instead of a vaccine that teaches the immune system how to build its own force of disease-fighting antibodies, such treatments provide a temporary shot of on-demand protection or treatment.
Once scientists began to create antibodies from living cells in the laboratory in 1975, the focus began to drift toward other diseases. The first licensed antibody drug was for kidney transplant recipients, blocking patients’ immune systems from attacking the new organs. Autoimmune diseases and cancer became a natural target for these drugs that were built by biology and were hard to discover and expensive to produce.
Until recently, Crowe said, “people found it just kind of an academic curiosity that one would make antibodies for infectious disease, because it was hard to envision” because of the high cost. In 2017, Crowe founded a biotechnology company, IDBiologics, with a focus on creating monoclonals for infectious diseases.
Special circumstances made a few diseases tractable. Synagis, an antibody drug that protects high-risk infants against respiratory syncytial virus infections, was approved in 1998. RSV turned out to be a good target, Crowe said, because babies need only a small dose to be protected. A longer-lasting RSV antibody is being reviewed by U.S. regulators.
Fear of Ebola, after 11 cases of the hemorrhagic fever were treated in the United States amid an outbreak in West Africa that began in 2014, helped catalyze investment in an antibody cocktail developed by Regeneron Pharmaceuticals in partnership with the U.S. government.
To make this approach practical for more infectious diseases, especially those primarily afflicting the global south, scientists are focused on finding or building ultra-potent antibodies and making manufacturing more efficient.
If a small dose packs a big punch, doctors will need less medicine for each patient, reducing cost. A smaller dose also will allow the drugs to be given as injections, rather than as time-consuming IV infusions.
“There need to be some breakthroughs in terms of driving down the cost of goods,” said Jacqueline Kirchner, a senior program officer at the Bill & Melinda Gates Foundation. “I think we’re at the early stages of realizing that promise.”
‘Pretty amazing’Kassoum Kayentao, one of the leaders of a trial that found an antibody treatment could prevent malaria, explained the research to community leaders and residents in Kalifabougou, Mali. (Peter Crompton/National Institutes of Health)
When scientists announced in October that a monoclonal antibody was 88 percent effective in preventing malaria in adults, scientists were buzzing — but not about that drug.
Instead, the news augured well for another, more potent next-generation antibody drug being tested in children in Kenya and Mali. That medicine could be given by a more convenient injection, rather than by an IV.
Robert Seder, the chief of the cellular immunology section at NIH, said he began testing the second-generation version in tandem with the first because he knew that even if the first worked in a trial, it wasn’t going to work in the real world.
“I was already thinking you need to have something more potent that would be cheaper,” said Seder, who has been in talks with Yusuf Hamied, the chairman of the Indian generics company Cipla, to explore whether an Indian pharmaceutical company could manufacture the drugs at a reasonable price.
Hamied is famous for challenging Western pharmaceutical companies by offering two decades ago to make HIV drugs for low-income countries for a small fraction of the price. Cipla doesn’t make biologic drugs, which are more expensive to produce than the small-molecule HIV drugs, but Hamied said he thinks it can be done at a reasonable cost through a partnership.
“I don’t like to lose money, but I don’t mind not making money,” Hamied said.
Malaria illustrates that even with much-needed vaccines, antibodies could play a role in saving lives. A long-awaited malaria vaccine was approved in 2021, but it was not highly effective, and there isn’t enough of it. About 18 million doses are projected to be manufactured in the next three years.
Typically, academic and government scientists strive to show an experimental drug is effective and then hand the research off to drug companies. But in the case of malaria, lab scientists also are trying to prove that a drug could be a successful product. R. Scott Miller, the clinical development team leader for the malaria program at the Gates Medical Research Institute, said that early in the process, scientists are asking basic logistical questions. Can it be administered with a shot? Does it require cold storage?
Improved technology has accelerated the search for ultra-potent antibodies. One method involves taking the blood of people who have survived an illness and identifying the antibodies that are best at blocking a pathogen. New tools, such as the ability to study individual immune cells that secrete antibodies, have supercharged this discovery process.
“We used to make a dozen [antibodies]; we thought that’s pretty amazing, and it would take us two years,” Crowe said. “Now, we could make 15,000 in two weeks” from a single person who survived Ebola.
Robert F. Garry Jr., a virologist at Tulane University School of Medicine, said he started working on monoclonal antibodies for Lassa, a hemorrhagic fever that causes thousands of deaths each year in Africa, with the goal of creating better tests to diagnose the viral illness.
But when Garry and his colleagues studied the blood of Lassa survivors, they discovered something even better: potent antibodies capable of blocking the virus from entering cells. One of the most potent antibodies came from a nurse who worked in a Lassa ward and had been infected and repeatedly exposed to the virus.
“The thought, originally, was those are going to be really expensive to make, and they’re not going to be accessible to populations in low- and middle-income countries. But we specifically went after these antibodies so they’d be potent at low doses,” Garry said, noting that a cocktail of antibodies he has been developing against Lassa is about 50 to 100 times as potent as the one against Ebola, requiring a far smaller dose. Garry co-founded a company, Zalgen Labs, to work on therapeutics for viral hemorrhagic fevers, including Lassa.
Other scientists are using engineering to increase the potency of antibodies. Jean-Philippe Julien, a biochemist at the University of Toronto, has been working on developing “multabodies” — building a scaffold that can hold many antibodies and launch a multiprong attack on a pathogen. Instead of binding to a single spot on a pathogen, a multabody can bind like a strip of Velcro. One candidate that his lab developed to fight the coronavirus was 10,000 times more potent than a single antibody.
“The cost of goods is at the forefront of our thinking,” Julien said. “If you can have something that’s more potent, does that mean you can administer less, such that you shave the cost?”
Even further down the line, scientists are thinking more radically about how to change the means of production. At the moment, cells harvested from Chinese hamster ovaries — grown in giant vats that have to be precisely controlled — are the workhorse of monoclonal antibody production. The process could be made more efficient by using a different, faster-growing and less fussy type of cell, such as yeast or fungi.
“If I can do it faster and with less stuff, it’s cheaper,” said J. Christopher Love, a professor of chemical engineering at the Massachusetts Institute of Technology working on developing systems that turn different types of cells into antibody factories. “Think about brewing beer.”
Even advocates of using antibodies for infectious diseases aren’t sure what role they ultimately will play alongside vaccines and other treatments. But they reject the idea that the drugs are too costly to be considered.
“I have sort of an optimistic hope — I wouldn’t call it a belief yet — that we’re at the beginning of something different,” said Eric Goosby, an international infectious-diseases expert and U.S. global AIDS coordinator under President Barack Obama. “I don’t know if I’m naive, but I feel that it is still figure-out-able, and we’re smart enough to do that as a global community.”