Though the peak of COVID-19 deaths is thankfully behind us, the virus is still a pernicious public health threat that vexes drugmakers by constantly evolving new variants that can elude existing treatments.
“We were just looking at the weekly death rates, and there are still over 500 people a week who are dying from COVID,” Gary Nabel, M.D., Ph.D., co-founder, president and CEO of ModeX Therapeutics, told Fierce Biotech in an interview. “That's pretty close to the number of people that are dying from flu.”
In an effort to “box in” SARS-CoV-2, ModeX and partners at the Vaccine Research Center (VRC) have designed multispecific antibodies that they’ve found can neutralize many current COVID strains and prevent the virus from evolving methods to escape the drugs. In the proof-of-concept study, published in Science Translational Medicine on Oct. 9, the antibodies were also able to protect hamsters from developing serious disease when exposed to omicron variants.
Nabel’s first foray into antiviral multispecific antibodies was during his tenure at Sanofi and targeted HIV, another shifty virus known to evolve drug resistance. That work was also done in collaboration with the VRC, a research program that sits within the National Institutes of Health’s National Institute of Allergy and Infectious Diseases, which Nabel directed from 1999 to 2012.
ModeX launched in 2020 and teamed up with the lab of Nancy Sullivan, Sc.D., an infectious disease expert who previously developed antibodies for Ebola virus, to go after COVID-19. Sullivan was at the VRC at the time but is now the director of the National Infectious Diseases Laboratories at Boston University.
“When [Nabel] suggested partnering to build these antibodies against COVID, we were very enthusiastic,” Sullivan told Fierce in a joint interview with Nabel. “Because ModeX had developed the technology to develop trispecific [and] tetraspecific [antibodies].”
Modex’s antibodies contain multiple binding sites and can target several parts of SARS-CoV-2’s spike protein, the tool the virus uses to infiltrate our cells. Multispecific antibodies the team tested successfully shut down the replication of the original COVID-19 strain, as well as beta, delta and omicron variants, in a lab test using human cells.
One trispecific antibody, 61.1/46.1-182.1, was more effective against an omicron subtype than GSK’s monoclonal antibody Xevudy (sotrovimab).
“The trispecific was developed before omicron” emerged, Sullivan said. “Then we found that it neutralized omicron. That is the idea, that you have, for lack of a better word, a universal antibody.”
Sullivan next performed some experimental evolution, exposing generation after generation of virus to 61.1/46.1-182.1 to see whether the pathogen eventually became able to evade the drug. In three independent experiments, the virus failed to evolve an escape route.
“If you don't get resistance within several rounds of replication, it's very difficult for that virus to develop resistance,” Sullivan said. She also noted that the multispecific antibodies tended to clump together into aggregations, “which you can imagine is not good for the virus.”
The researchers then designed another trispecific antibody and tested whether it could be used not just to treat COVID, but to prevent it. Syrian golden hamsters given the antibodies and then exposed to omicron variants of SARS-CoV-2 had lower levels of the virus in their lungs and noses than hamsters given just saline solution.
“To have one antibody molecule that you can use prophylactically as well as therapeutically is a big advance for the field,” Sullivan said.
With these prototype antibodies proven effective, ModeX is now advancing newer versions of them into the clinic with the help of the Biomedical Advanced Research and Development Authority (BARDA). BARDA initially gave the biotech up to $168 million to develop the antibodies in late 2023. That funding has now been supplemented with an additional $35 million, the company announced on Oct. 7.
“The first prototype has four binding sites and is tetravalent, and that's ready to move forward,” Nabel said. “We're hoping sometime next year to be able to get it to phase 1.” The new BARDA funding will go towards advancing a second antibody for COVID-19 and toward ModeX’s efforts to deliver the antibodies genetically, whether through DNA or RNA, he added.
Because of ModeX’s progress on SARS-CoV-2, BARDA has also unlocked a further $16 million for the company to develop an antibody program for influenza.
“We have essentially the first tranche of funding to bring prototypes that can neutralize some of the highly pathogenic avian influenza viruses, and it turns out, also will hit many of the seasonal strains,” Nabel said. ModeX is now working to identify a lead flu antibody candidate.
When it comes to COVID-19 work, Nabel emphasized the importance of moving quickly. Antibodies developed during peak COVID by Regeneron, GSK and AstraZeneca, for example, don’t work against newer variants of the virus, he said. Once the acute phase of COVID infection passes, many go on to develop long COVID-19.
“I've seen numbers estimating hundreds of millions of people who have Long COVID,” Nabel said. “We know that some of those people have persistence of virus in their blood. One of the other indications we'd like to explore would be whether or not these antibodies might be helpful at least to some proportion of patients that have long COVID.”