U of T researcher says lab has developed antibody to ‘cure’ virus.
The scientist sprinkles his conversation with punchy quotes.
“Everything seems impossible until it’s done.” Nelson Mandela.
“You gotta use what you got to get what you want.” James Brown.
“If the left hand don’t get you, the right one will.” Muhammad Ali, quoting Tennessee Ernie Ford.
But, when Sachdev Sidhu talks about what his team has accomplished in its lab at the University of Toronto’s Donnelly Centre for Cellular and Biomolecular Research, the words are entirely his own. And they stun.
A cure. For the coronavirus. For SARS-CoV-2. For the COVID-19 disease that has killed upwards of 320,000 people around the planet. A knockout punch. “Yes, I believe ‘cure’ is the proper word,” the molecular engineer says, almost blandly. “They would no longer be ill. They would no longer have the virus in their system. That’s a cure.” He’s done it. He’s certain. Invented a synthetic antibody to eliminate the symptoms — from mild to severe — that have sickened five million people worldwide.
At the least, he says he’s kept pace with such multibilliondollar pharmaceutical giants as Regeneron, fast-tracking clinical trials of its own therapeutic antibody as a potential remedy for COVID-19.
“We both would eliminate the symptoms,” Sidhu explains in his office on College Street. “Our antibody keeps the virus from getting into a cell.”
The paradox of frantic research amid a pandemic is that urgency still demands patience, trial and error. Most potential breakthroughs fail. Yet Sidhu insists that his antibody — taken from E. coli bacteria and then grown in a Chinese hamster’s ovary cells and formally called 15033 because it’s literally the 15,033rd antibody his lab has concocted over many years — could be mass-produced within a month, maybe two, if federal health and research gatekeepers sign off.
“We’re already talking to a few pharmaceutical companies. We’re trying to figure out, what’s the best way to scale it up? We’re also talking to the government. If they want to kick in some more money, we can keep it more Canadian and independent. Because now the question is, how do you make literally tons of it?
“It’s kind of like making beer in vats. Clean out the tanks and do it again a few weeks later. Give us millions of dollars and we’ll give you kilograms of the drug.”
To hit his aggressive timeline, Sidhu needs government support. Indeed, scientists at a National Research Council of Canada facility in Montreal are discussing working with him, an NRC spokesperson confirmed. An early step.
Skip the animal-testing stage, Sidhu all but pleads. No reason to kill a bunch of monkeys.
Because he’s “99 per cent sure” 15033 will work.
To be clear, this is not a vaccine. Even if it works, it won’t prevent infection. Moderna Inc. on Monday announced its potential COVID-19 vaccine, the first to be tested in the U.S. — showed it had produced protective antibodies in a small group of healthy volunteers. Multiple vaccines are being evaluated internationally. One might hit the jackpot. Or not. In nearly four decades of massive research, no vaccine for HIV/ AIDS has been discovered.
“The only way you can really test the efficacy of a vaccine is giving it to a large population and then wait several years,” says Sidhu. “Nobody knows how long a vaccine is going to be effective. Either it will change the game or it won’t change the game. It’s a roll of the dice.”
Waiting for a vaccine would make sense if there were no alternative, Sidhu says — but his antibody is a different tool in the tool kit.
The molecule, Sidhu says, could be injected into seriously ill patients and keep them off ventilators, which may actually be killing them — as many as two-thirds won’t survive mechanical ventilation. “It should literally start working right away. There’s millions of viruses and, for people who have a very severe disease, our antibody hits every single one of them. That’s what a good antibody does. So, it’s basically a kick in the teeth for the virus.”
Sidhu’s lab was among 47 research teams across Canada that received $27 million in emergency federal government funding in late February to accelerate their work, a group culled from 227 applicants. For Sidhu’s bunch and their cutting-edge laboratory advancements, the two grants received — totalling $1.3 million over two years — were a shot in the arm for which he is immensely grateful.
“Working with my collaborator, Jim Rini, my lab in one month went from nothing to an effective inhibitor of the virus. Granted, as a cell-based assay.” An analysis. “But another thing about this virus is the cell-based assays are very indicative of the virus itself.”
This project built upon advancements already achieved in Sidhu’s lab, including by then post-doctoral student Wei Zhang, who four years ago gained major research props for developing synthetic ubiquitins that act as antiviral agents against pathogens such as Ebola, SARS and MERS. Sidhu has worked on all those horrific pathogens, as well.
“There’s more and more data coming out that a strong antibody response correlates with successful recovery.” Which isn’t the hotly pursued magic bullet, but it is ammunition. (Sidhu notes that “magic bullet” was first coined by German Nobel laureate Paul Ehrlich, founder of chemotherapy — 100 years ago.)
“The amazing fact is that we don’t all die from infectious diseases.” Because the body can naturally defend against most bugs. “With my group, over the last 20 years, antibody engineering has become a fine — I was going to say art, but it’s not art. It’s gone from science to engineer, the definition that precisely defines the science we do.”
He looks the genius part, a little dishevelled, grey-streaked hair spurting in messy coils. For an unbrilliant inquisitor, he strives to simplify the science. Although he maintains attacking the coronavirus was a far less complicated endeavour than taking on, say, HIV — a retrovirus that integrates with the cell’s genome — or Ebola.
“It’s less complicated because its life cycle is less acute. Ebola, for example, is a terrible virus. But it’s better than HIV because it goes in quickly — you’re either dead or you’ve recovered. You know when people have Ebola.” It’s a hemorrhagic disease, after all. “Those who contract it bleed from the pores, from the eyes.”
The coronavirus is, says Sidhu, somewhere in the middle. “It’s hard to know when people have it. Fortunately, it’s less lethal. The only question is, will it last forever?”
In a nutshell, 15033, Sidhu says, neutralized the virus in their analysis. “We have definitive proof of that. And we did that in 33 days. Other groups out there are doing the same thing. But I think we’re one of the most advanced.”
Working in collaboration with Washington University in St. Louis, which provided the live virus in human cells, the next step would be introducing the synthetic antibody to those with COVID-19. Will it eliminate the symptoms and prevent death? Again, Sidhu has no doubt.
“We have to do the final test in humans. But, in a way, the science part is done. I don’t have any questions anymore.”
OK, cut to the chase. How did you do it, Professor Sidhu? He smiles. “That’s why I get the big bucks.
“No, seriously. That’s my field. We know the principles. Before my team thought of it (the synthetic antibody) in the lab, it didn’t exist. It requires a fundamental understanding of how proteins work. We build it. I can’t describe it any better than that.”
Except, small detail, Sidhu’s team had some 10 billion antibody molecule choices for experimentation, 10 billion different antibodies in a single tube of stuff. “Quite boring actually. Just sitting on a bench.”
Those 10 billion antibodies are represented in one-tenth of a millilitre of “buffer” and then, using a process called phage display — the technique was awarded a Nobel Prize in 2018 — they’re tested. The process is all done in a few millilitres. “It’s embarrassingly simple,” Sidhu says.
“You take your virus, you stick it at the bottom of a plate, you add those 10 billion antibodies. The ones that bind to it will stick. And you wash them with buffer, which is essentially water.” Then, he says, the ones that remain stuck are used to make a new set of antibodies.
“It’s important to understand this is truly synthetic in that there was never an active source. We physically made the synthetic DNA,” Sidhu says. “Other groups are trying to clone it out of mice, out of people. We don’t do that. That’s why we think it’s better, because ours is much more engineerable. We designed it ourselves.”
Of course, the coronavirus can mutate, indeed it has. Not a game-breaker, says Sidhu.
He emphasizes: “This is not guesswork. One thing I can guarantee is, if any mutant arises, we can develop a new and better antibody.”
For clinical trials, Sidhu figures he’d need 300 to 400 patients. “There are thousands of people in the hospital in Toronto alone. We can find those people.”
Further — this too is crucial — the virus is a foreign invader; it’s not arising from within the body, like cancer. “With cancer treatments, you’re not just going to hit the cancer, you’re going to hit other tissues. Cancer therapy is very hard on the patient. Here we don’t have that issue. We can dose the antibody very high. The drug hits it hard and doesn’t hit anything else. I’m very confident it’s safe.”
Still, the lab will be doing small animal tests for safety over the next few weeks.
Whither after that depends on the Canadian Institute of Health Research and gobs more funding from Innovation, Science and Economic Development Canada.
“Drug development has a lot of logic but sometimes very little common sense,” Sidhu observes. “A normal human being would say, ‘OK, you’ve got a drug, not guaranteed but very likely to work. Check. You’ve got a million people who need that drug. Check.’ Well, Health Canada or the (Federal Drug Administration, in the U.S.) will immediately go to a big book that says, well you can’t do that because of these rules.”
The precedent has been set, however, with plasma testing as a therapy for COVID-19, which quickly went into human trials, including in Canada.
Sidhu agrees entirely with a more methodical and cautious approach for human testing. Except this crisis has changed the landscape with the strong possibility of a second COVID-19 wave on the horizon. “When you’re dealing with something like arthritis, where in six months people aren’t going to die, you might as well be absolutely certain. But, when you’re dealing with a disease that is this crucially infectious, the longer you wait the more people will have it. Then you don’t want to do unnecessary tests, or even things that might be necessary in another environment.”
How confident is Sidhu about 15033? He reaches for another sports metaphor: One of the greatest plays in NBA history, Michael Jordan’s game-winning shot with 5.2 seconds left to put the Bulls up 87-86 over the Jazz for Chicago’s threepeat-repeat championship.
“The only way to know for sure is when Michael Jordan drains that last shot. Then you’re pretty sure it’s game over.”
Sidhu wants to take that shot.