As drugmakers race to design new therapies against COVID-19, many are opting to develop neutralizing antibodies that target the spike protein on the surface of SARS-CoV-2, the virus that causes the illness. Now, less than two months after teaming with AbCellera to develop neutralizing antibodies to fight the novel coronavirus, Eli Lilly has signed on a second partner to join its efforts to defeat the virus.
Lilly has agreed (PDF) to pay $10 million upfront and committed up to $245 million for ex-China rights to co-develop and sell neutralizing antibodies from China’s Junshi Biosciences. Junshi’s lead candidate, dubbed JS016, is a recombinant fully human monoclonal antibody. The pair aims to apply to start a clinical trial in the U.S. in the second quarter.
The deal marks the latest of at least five other programs aimed at developing neutralizing antibodies against the SARS-CoV-2 spike protein, which binds to the host cell surface receptor ACE2 to help the virus enter and infect human cells. The hope is that neutralizing antibodies will be able to interrupt that interaction, even if the virus mutates to a more virulent strain, as some researchers fear may already be happening.
Developing neutralizing antibodies promises to be a faster approach than designing a new small-molecule drug would be, but getting from idea to an effective product may not be so simple. Amid the intensifying deal-making around COVID-19 drug development, scientists are raising concerns that the virus may find ways to outsmart neutralizing antibodies, which would no doubt complicate the effort to find therapies that are both safe and effective.
For example, in a perspective published recently in the International Journal of Biological Sciences, two Chinese scientists suggested that that treating COVID-19 with a cocktail of multiple neutralizing antibodies—each targeting different epitopes on the spike protein—might be required to conquer the virus. They cited previous studies showing that antibody cocktails exhibited stronger viral neutralization than any antibody alone in Ebola and SARS-CoV, the latter of which was a coronavirus that sparked an outbreak in the early 2000s.
Regeneron, in fact, is taking the cocktail path, having identified two such therapies by selecting from hundreds of neutralizing antibodies found in mouse models and people who have recovered from COVID-19. The company has started large-scale manufacturing and expects to launch in-human studies with the lead cocktail in June, CEO Len Schleifer said during a conference call after the company announced first-quarter earnings on Tuesday.
Several other biopharma companies are working on antibody solutions against the new virus that causes COVID-19. GlaxoSmithKline has paired with Vir Biotechnology to advance two candidates, VIR-7831 and VIR-7832. AstraZeneca is evaluating antibodies from three sources: patients who have recovered from the disease, humanized mice and phage display. Amgen is working with Adaptive Biotechnologies to develop treatments, and Korea’s Celltrion has identified 14 antibodies, aiming for clinical trials in July.
But even if solo antibodies or cocktails show early signs of efficacy, other risks could come into play. For one, the treatments could backfire in a phenomenon called antibody-dependent enhancement (ADE), in which a virus takes advantage of antibodies to enhance infection. The problem is well-known in dengue: Sanofi’s Dengvaxia carries a warning stating that administering the vaccine to people who have not previously been infected with dengue raises the risk that they may get a severe form of the disease if they are subsequently exposed to it.
In a recent Journal of Virology study, a group of Chinese scientists suggested that ADE events could happen with COVID-19 neutralizing antibodies, too. They demonstrated that in SARS-CoV and one other notorious coronavirus, MERS-CoV, neutralizing monoclonal antibodies that bind to thereceptor-binding domain of their respective spike proteins could actually facilitate the entry of the viruses into human cells.
During Regeneron's conference call, Chief Scientific Officer George Yancopoulos played down the potential that ADE would come into play with its COVID-19 antibody candidates. “When you have highly potent neutralizing antibodies, these risks are mitigated,” he said. In addition to its two chosen treatments, the company is developing cocktails made with antibodies that target “uber stealth constant regions, which would completely mitigate ... that possibility,” he said.
Eli Lilly has not yet provided details about its newest effort to develop drugs to treat COVID-19, but the company's chief scientific officer, Daniel Skovronsky, is optimistic the neutralizing-antibody approach will prove useful in protecting a wide swath of the population against the virus. “The data generated by Junshi Biosciences suggest the lead antibody may have appropriate properties to support testing its therapeutic use in patients as well as exploring its potential for preventing infection in at-risk individuals,” Skovronsky said in a statement.