Neutralizing ground

Hopes are high for the Covid-19 molecular antibodies heading into clinical trials.

Crystal structure of SARS-CoV-2 receptor binding domain in complex with human antibody CR3022

Before, or maybe after, we get vaccinated against Covid-19, millions of us eventually may get another biologic drug for the coronavirus, made of synthesized proteins known as monoclonal antibodies (mAbs). Clinical trials are underway for many mAbs created to treat the disease, and many of these studies could yield results quicker than vaccine trials because the mAbs are given right to people who have the virus.

Some background:

We don’t yet have direct public evidence that any Covid-19 vaccine candidate works in humans. We do have evidence that the vaccines produce significant amounts of “neutralizing antibodies”—proteins churned out by immune system B cells that can slow or stop an infectious disease. In this case, the proteins bind to the SARS-CoV-2 virus’s spike protein, the molecular crowbar by which the virus enters cells.

People who survive the disease carry these neutralizing antibodies in their blood, at least for a while. That’s the mechanism behind “convalescent plasma” transplants, using blood from these recovering patients.

Convalescent plasma transplants have been widely used for more than a century for diseases that lack drugs and these transplants are generally considered safe if not necessarily effective. So in addition to the turbocharged global march toward Covid-19 vaccines for prevention, dozens of clinical studies are looking at convalescent plasma.

The jury is still out on how well this approach will work. And as with any blood transplant, the logistics are tough, the supplies are limited and each transplant will work a little differently.

But mAbs that act as neutralizing antibodies may offer a better route.

Dozens of mAb drugs have been approved, mostly for cancers. And we have an astonishing toolkit for precisely designing and testing these biological beasts, and churning them out in volume. So labs in academia and pharma have been rapidly developing Covid-19 mAbs: plucking out B cells from survivors’ blood, analyzing the antibodies these cells produce and how well they work to shut down SARS-CoV-2 infection, testing huge volumes of mAb variants, optimizing their neutralizing characteristics and coming up with the best candidates for clinical trials.

Last week in a webinar hosted by The Scientist, James Crowe of the Vanderbilt Vaccine Center and Joseph Jardine of the Scripps Institute and the International AIDS Vaccine Initiative (IAVI) outlined two round-the-clock initiatives that led to mAb candidates, described in Nature and Science.

The main goal is treating patients with Covid-19. But both groups also hope the drugs will guard other groups at high risk, such as the elderly.

Aside from maybe arriving months earlier, how will mAbs compare to vaccines in preventing Covid-19?

As with vaccines, the biggest question may be how long mAbs remain effective.

In Covid-19 patients, levels of neutralizing antibodies drop off fairly quickly. “That’s concerning; it’s not what you’d like,” says Jardine. The hope for survivors (and people who receive vaccines) is that B cells will remember the threat and ramp up production of neutralizing antibodies again if needed, which seems likely but apparently isn’t proven.

In contrast, mAbs simply don’t last indefinitely. Jardine commented that if they are suitably tuned up, these drugs might deliver protection for three to six months or so.

Crowe suggested, however, that mAbs might actually work longer than vaccines, noting that two of his group’s mAb candidates hung on surprisingly well when tested in rhesus macaques. These drugs probably also will perform well among the elderly, whose immune systems often struggle to produce suitable flows of antibodies.

Moreover, mAbs may come with fewer safety concerns. “Vaccines are pretty complicated, and they have complex safety profiles,” Crowe said. “Antibodies generally have a very high safety profile.”

Both researchers predicted that the newfound ability to quickly whip up targeted mAb drugs and test them in the clinic also may prove invaluable for other infectious illnesses.

“Antibodies increasingly will be a major part in the future of preventing and treating infectious diseases,” Crowe declared.

Jardine emphasized IAVI’s goal to bring mAb technology into lower and middle-income countries (LMICs) as well. “If we can make this viable for LMICs with Covid-19, we should be able to use it for other things like HIV,” he said.

Top, crystal structure of the business end of SARS-CoV-2 bound to a human antibody