Sorrento Responds to Criticism of COVID-19 Neutralizing Antibodies

The biopharma industry is receiving very close attention by the public and investors due to the global COVID-19 pandemic. In addition, the medical and scientific community has embraced the adoption of scientific study preprints during the pandemic. A Nature Biotechnology op-ed notes, “The burgeoning adoption of preprints by the medical community in recent months underscores their importance as a means for rapid sharing and updating of research findings during an outbreak. In the longer term, it also may provide a watershed moment, signaling the arrival of preprints as a legitimate complement to peer-reviewed journals, broadening their acceptance among a wider community of researchers, and accelerating their integration into journal publishing workflows.”

With that, there is a lot of questionable research about COVID-19 gaining attention. Also, companies, many in ways consistent with standard business practices, are regularly issuing press releases related to their ongoing work related to the pandemic. Others, however, appear to be connecting company news to COVID-19 in any way they can in order to garner media attention amidst all the pandemic noise. Some media sources, as well, are jumping on any positive COVID-19 news in a way that may overinflate the actual scientific research.

As a result, some of the analysts, researchers and life sciences media are becoming particularly analytical about media reports of COVID-19 news, not only looking for inaccuracies, but for trumped-up press reports that may be a way to inflate company stock price, a so-called “pump and dump” scheme.

On May 8, San Diego-based Sorrento Therapeutics announced it was teaming up with New York City-based Mount Sinai Health System to develop an antibody cocktail called COVI-SHIELD to treat COVID-19. The partnership is aimed at creating antibody products that could act as a “protective shield” against infection by the virus that causes COVID-19, SARS-CoV-2. COVI-SHIELD is expected to deliver a mixture of three antibodies that combined recognize three specific regions of the SARS-CoV-2 Spike protein.

The organizations believe that, if approved, COVI-SHIELD could be given for people returning to work and as a therapy for people exposed to the virus.

A week later, Sorrento announced that one of its antibodies, STI-1499, had shown 100% inhibition of SARS-CoV-2 in laboratory tests. Henry Ji, Sorrento’s co-founder, director, president and chief executive officer, and Mark Brunswick, vice president of Regulatory Affairs and Quality, took time out to speak with BioSpace ahead of the announcement.

In that interview, Ji said, “We screened about a billion antibodies. And we found about 100 of them to characterize further. From them we selected about a dozen that had neutralizing activity.”

Then, working with collaboration partners at the University of Texas Medical Branch, which has access to the live virus, they were able to screen the dozen antibodies for the most promising ones.

“We’re actually so impressed with the data,” Ji said. “One of the antibodies is so powerful that at a very low concentration it is able to 100% completely prevent infection or inhibit the infection. In our studies, not even one virus escaped from the antibody.”

It would not be unusual for a biotech company to announce a business and research partnership, such as the one with Mount Sinai. It would also not be particularly unusual for a follow-up indicating an advancement in that research project, such as the identification of an antibody. What makes this story particularly newsworthy, especially outside the bubble of biopharma and life science journalism, is the COVID-19 pandemic.

At no point in the BioSpace article or during the initial interview did Ji or Brunswick refer to or use the word “cure” to describe their research. In a FOX News interview, however, Ji is quoted as saying, “We want to emphasize that there is a cure. There is a solution that works 100%.”

Several analysts and media pounced, partly because Sorrento’s stock immediately climbed from $2.62 per share to $9.96 per share, before it dropped back down to $5.23 Tuesday morning.

In a new BioSpace interview on May 21 with Ji and Brunswick, Ji emphasized the stringent process the company went through in identifying STI-1499, noting that in the antibacterial and antiviral space, the laboratory testing to prove antibody efficacy is generally higher than for vaccines and oncology—with 100% elimination of the virus in human cells required.

“For perspective,” Ji says, “these antibodies, if you do ELISA, you will have binding activity. Same as a vaccine. Using a vaccine, you have an ELISA test of your blood, you have antibody in it. But most of the antibodies are not neutralizing.”

The next step by Sorrento was from 500 to 600 antibodies, they screened for neutralizing antibodies, testing for their blocking activity. Out of those antibody clones, they found about a dozen that were neutralizing.

“If you go back to vaccine, in parallel, after you get the antibody, you want to see if there’s a neutralizing antibody. From those ELISA-positive antibody-binding antibodies, we got to a dozen that were neutralizing in vitro. Then we asked, Are they really doing their job by blocking viral infection in the real setting?” Ji said.

Most labs don’t have access to the real SARS-CoV-2 virus, so they use reporter systems with pseudo-viruses. That is to say, other types of viruses with the spike (S) protein or other proteins grafted onto them, to mimic the antigen profile of the virus. If these provide 50 to 60% antibody activity, it is usually called a success. It gives you a hint, but it’s still a question of if it’s real.

Sorrento worked with the actual virus at the University of Texas Medical Branch and found 100% neutralizing activity with the specific antibody in question. They incubated them in human cells for four days. They are looking for what is called cytopathic effect, or CPE, which is structural changes in host cells caused by viral invasion.

“In the live virus test, we mixed the virus for one hour and then incubated with healthy cells for four days. Under the microscope, you see CPE, which tells you if there are any infections. If you have a single CPE, then it’s positive for infection,” Ji said. “So the bar is very high. You can’t even have a single active virus infection. You have to be complete, 100%. Of course people say, ‘Nothing is complete.’ They don’t understand. It has to be 100% in these tests.”

“If you have complete prevention after four days, I will believe the data,” Ji said. “Otherwise, I will not believe the data.” After four days, there was only one antibody that at very low concentrations prevented 100% of infections.

“No single cells have CPE,” Ji added. “That’s a very big deal. In the cancer space, we see in mice, in cancer antibodies, we have 100% tumor suppression, 100% eradication. We never report it. You know why? Sometimes mice, you can cure cancer in mice, but it doesn’t translate into humans at all. But in antibacterial and antiviral research, petri dish data is very correlating to in vivo data. So you need to have 100% prevention and suppression of the infection. If not, you don’t have a very good compound.”

Ji added, “It’s a requirement for antiviral and antibacterial work, you have to have 100% suppression, or you don’t have a good compound. That’s our position. We believe we have a very good compound. After that, it’s all execution, how to get it safely approved and distributed.”

He also insists that they did not say it was a cure, but “if it gets through safety studies, if it demonstrates efficacy, it potentially is a cure—if you have the antibody in the blood and it prevents infection. After virus infection, if it blocks the virus from replicating in healthy cells continuously, you might have a cure. We cannot cure the late-stage patients, on ventilators, because of all the other comorbidities and complications. Those are not the job of the antibodies.”

Brunswick adds, “In late-stage patients, while we might be able to remove the virus from the patient, the damage from the virus may be too much for the patient to clear on their own. We have not gone into any patients yet. It’s all speculation based on our in vitro data. We were very clear this was all based on in vitro data.”

Ji concludes, “Right now we’ve found a good antibody. We’re doing everything we can to execute, to get into IND filings, to get into humans, and if it shows safety and efficacy, we’ll try to get this product approved and onto the market. We’re also focusing on scaling up our manufacturing. We have a cGMP facility that can produce up to 100,000 doses every month. So, we’re looking for a partner to get to 1 million doses.”

And to the overall criticism, Brunswick says, “We just want to emphasize we are not ‘pump and dump.’”

Nor is this the only prominent case of the high level of scrutiny and pushback companies are starting to get in COVID-19-related news.

On Tuesday, May 18, Moderna released positive interim Phase I data from its clinical trial of mRNA-1273, its mRNA vaccine against SARS-CoV-2, the novel coronavirus that causes COVID-19. The company reported overall positive results for both efficacy and safety, although not a lot of details were released on the actual data.

The company’s stock rocketed, hitting a stock valuation of $29 billion. Several vaccine experts, however, expressed criticism of the data, or lack of it. Some of the experts, speaking with STAT News, noted that Moderna’s partner, the U.S. National Institute for Allergy and Infectious Diseases (NIAID), was noticeably silent on the data, neither issuing a press release nor providing comment.

STAT and the vaccine researchers noted that, “all 45 subjects (in this analysis) who received doses of 25 micrograms (two doses each), 100 micrograms (two doses each), or a 250 micrograms (one dose) developed binding antibodies. Later, the statement indicated that eight volunteers — four each from the 25-microgram and 100-microgram arms — developed neutralizing antibodies. Of the two types, these are the ones you’d really want to see.”

The problem, they go on to say, is Moderna did not release results from the other 37 trial participants. That doesn’t mean they didn’t develop neutralizing antibodies, but it makes it basically impossible to evaluate the overall data. They critics are not saying Moderna is hiding any negative results, but merely that Moderna provided the data they had and it’s not really enough for a real evaluation. This may be a way of saying that the Moderna release was publicity and news, but not necessarily science. Certainly, it had a positive effect on the company’s stock, and it’s completely true to say that the world is closely watching the results of the trial with a great deal of hope and optimism.

Another criticism is that the data is only two weeks old.

“That’s very early,” Anna Durbin, a vaccine researcher at Johns Hopkins University, told STAT. “We don’t know if those antibodies are durable.”

It’s worth pointing out that Moderna was releasing the news in a press release but had not yet submitted it to a peer-review technical journal. Or, for that matter, even released it preprint. A Moderna spokesperson indicated that NIAID would be publishing the full data at some time.

Another example of this kind of scrutiny, albeit of a slightly different nature, is when last week Paris-based Sanofi’s chief executive officer Paul Hudson indicated that the U.S. would have first access to its COVID-19 vaccine because of the significant financial support it is receiving from the U.S. government. This raised a furor in other countries, particularly France, where the company is headquartered, and the UK, where its partner in the vaccine endeavor, GlaxoSmithKline, is located.

Sanofi is now backing away from the pledge, where Hudson had said that because of the U.S.’s Biomedical Advanced Research and Development Authority (BARDA), part of the Department of Health and Human Services (HHS), funding, “The U.S. government has the right to the largest preorder because it’s invested in taking the risk.”

Although the statement at the time seemed fairly logical, Europeans did not see it that way. The office of French President Emmanuel Macron stated a vaccine is “a global public good, which is not submitted to market forces.”

The country’s Prime Minister Edouard Philippe tweeted, “Equal access for all to vaccine is not negotiable.”

Part of what is at issue is the world’s attention. To date, according to Johns Hopkins University of Medicine, the pandemic has confirmed infections of 5,034,458, and taken the lives of 329186, with 93,066 deaths in the U.S. alone. Everyone is paying attention to every news story in hopes of good news. Millions of people who wouldn’t normally know the difference between a virus and a bacterium are now avidly reading news stories about the virus, treatments and vaccines, and perhaps fancying themselves armchair virologists, epidemiologists and vaccine experts.

Skepticism is warranted. And people publicly speaking about work in the area, whether company executives, spokespeople, public relation firms, journalists and politicians, should measure their words carefully. The whole world is watching.