Amid alarming spikes in infections and a wave of new restrictions announced across Europe, some good news is emerging: Monoclonal antibodies are likely to be the first game-changing therapy against COVID-19.
Big drugmakers have ample experience in manufacturing these kinds of medicines, and their existing facilities can readily be converted to produce doses of a future COVID-19 treatment, experts say.
Mark Esser, vice president and head of microbial sciences at AstraZeneca, said his company had a history with antibody-based drugs, like the asthma medication benralizumab, or durvalumab for cancer. Earlier in the month, the British drugmaker announced that it would soon start two Phase 3 trials of its drug candidate AZD7442 — a cocktail of two antibodies. Interim results from the studies are expected in the first half of 2021, Esser said.
In other cases, timelines are shorter. Regeneron, the developer of the antibody therapy administered to U.S. President Donald Trump, has already applied for emergency use registration with the U.S. Food and Drug Administration. As has Eli Lilly, which said it was going to greatly expand its already-existing commercial production of its monoclonal antibody, together with the Bill & Melinda Gates Foundation, in April.
The hope is that these therapies can serve as a bridge until widespread vaccinations are possible, as well as help people who can’t be immunized for health reasons.
There are limitations, however. For one, monoclonal antibodies aren’t cheap. Doses of existing antibody drugs run into the tens of thousands of euros. Furthermore, the first generation of antibodies is likely to require large amounts of ingredients, meaning that the total number of initial doses will likely be small and restricted to those who need it most.
Then there’s the issue of access. As with vaccines, health experts fear that developed nations will monopolize access, leaving poorer countries out in the cold. That said, there are efforts — such as the Eli Lilly deal — to make sure that at least some capacity is reserved for developing economies.
Hamsters and ‘bioreactors’
Monoclonal antibodies are expected to be the first approved therapies specifically designed to counter coronavirus infections, setting them apart from repurposed drugs like remdesivir or dexamethasone, which have shown some effects in treating COVID-19 cases.
At this point, data is still sparse, but antibodies have already shown some promising early results. Experts say that they could also be administered protectively, providing some immunity to the disease, or at least shortening the length of the illness — a valuable benefit to frontline workers.
“The most common way to make them is with Chinese hamster ovary cells,” explained Lindsay Keir, innovations partner at the Wellcome Trust.
First, though, the desired antibody needs to be identified. Scientists can look at those produced either by people who have been infected with COVID-19 or through cell and animal experiments in the lab. Once an antibody is found, cells can be genetically modified to produce them.
These engineered cells are then grown in large stainless steel vats, called “bioreactors.” According to Keir, one batch of medicine might take 10 to 15 days, during which the teeming cells produce the desired antibody, as “a crude soup with a lot of other proteins.”
The resulting substance is purified and made safe for use, and then packaged into either an infusion or injection.
Emily Field, director and lead research analyst for European pharmaceuticals at the British bank Barclays, pointed to Big Pharma’s existing capacity in monoclonal antibody production as a valuable lever to get doses out of the factory and to patients quickly.
For example, Switzerland’s Roche AG — which is teaming up with Regeneron to help with production of its treatment candidate — is the biggest manufacturer and vendor of monoclonal antibodies in the world, she noted. With some work, this massive capacity can be converted.
Other drugmakers also stand ready to switch production should their antibody therapy get regulators’ sign-off.
Molly McCully, communications director for anti-COVID-19 therapies at Eli Lilly, said the company has numerous manufacturing sites worldwide. It has also secured external manufacturing capacity to supplement its existing U.S. and European plants.
“All of these sites have previously manufactured other monoclonal antibodies and have been converted to manufacture neutralizing antibodies for treatment of COVID-19,” McCully explained.
The catch: The drug is still the byproduct of living cells — which are more complicated than small molecule drugs like aspirin.
“We’ve seen frontrunners from Eli Lilly and Regeneron, but they’re using eye-watering high doses,” Wellcome’s Keir explained, adding that these first products might not be the ones that see widespread use. Later generations could be more effective, allowing for smaller individual doses — and so more medicine in every batch.
For now, though, limited doses could mean that they are reserved for frontline workers.
“What’s clear is that antibodies are difficult to make,” she said. “We don’t have a huge global capacity to manufacture millions or billions of doses to treat everyone.”
Big Pharma teams up
For now, drugmakers are working together to carry out research and get capacity online. Regeneron said it expects its deal with Roche to increase its capacity by at least three and a half times.
Daniel Grotzky, a spokesperson for the Swiss pharmaceutical company, said that Roche expects the first doses of the antibody to be ready in the first quarter of next year, with production based in California.
If demand were high enough, he added, the company could in turn outsource some production.
“But these efforts could still not meet very high global demand in all circumstances,” he conceded.
These kinds of agreements abound. U.K. pharmaceutical company GlaxoSmithKline is developing its antibody treatment with Vir Biotechnology, while an international coalition of Germany’s Merck KGaA, the Serum Institute of India and the nonprofit International AIDS Vaccine Initiative (IAVI) recently agreed to specifically develop affordable antibodies that can be sold in low- and middle-income countries.
Collaborations will likely be essential to making enough doses for everyone that needs one, said Keir.
“Regeneron’s antibodies look like they’ll be a success,” she said. “But they will only be able to make 50,000 doses, while treatment needs to look in the millions. It’s only through partnership that it’s possible to scale up the production.”
Janet Ginnard, Director of Strategy at Unitaid, a global health initiative that aims to treat major diseases in the developing world, sees grounds for optimism but also caution due to the complex production process needed to ensure global access.
“Thinking through the work to make sure they can be produced at scale, and deliver and reach those that can benefit, [is] not going to happen automatically,” she explained.
For now, studies are underway to try and determine the lowest effective dosages. This can help increase the yield of the medicine as well as make it more financially viable, she said.
There’s always the possibility of unexpected obstacles. Eli Lilly, for example, earlier in the month had its drug trial paused over safety concerns. A data and safety monitoring board is expected to review the trial data this Monday, when it will decide whether or not to resume enrollment for the study.
Barclays’ Field pointed to the complexity of the manufacturing processes and the need for extremely sterile conditions as a complicating factor. “I think the regulators take a very punitive view to any issues,” she said.