The U.S. government recently stopped distributing Eli Lilly’s COVID-19 antibody bamlanivimab as a single agent out of concern that it may not be effective against new coronavirus variants. But the drug’s original developer, AbCellera, believes it can still serve as a valuable component of combination therapies.
Among a panel of 24 antibodies identified from patients who recovered from COVID-19, bamlanivimab, also coded as LY-CoV555, showed the strongest ability to bind to and neutralize the SARS-CoV-2 virus that causes the disease in lab dishes. It also stopped the virus from replicating in the respiratory tract of monkeys, according to results published in Science Translational Medicine.
The data supports bamlanivimab as an effective therapy to treat and prevent COVID-19 when used early in infection, and when administered as part of a combination strategy, said Ester Falconer, Ph.D., AbCellera’s chief technology officer and senior author of the paper. “Bamlanivimab’s unique potency allows for lower dosing and enables administration with another antibody to address SARS-CoV-2 variants,” she said in a statement.
AbCellera scientists and collaborators originally identified 440 antibodies from convalescent plasma from a recovered patient and narrowed them down to 24 lead candidates based on a series of criteria such as the ability to bind to the SARS-CoV-2 spike protein, which the coronavirus uses to infect healthy human cells.
Among them, bamlanivimab was found to be able to bind a region of the coronavirus spike’s receptor-binding domain (RBD) that overlaps with the binding site of the ACE2 protein on human cells. It’s through the interaction between the spike’s RBD and ACE2 that SARS-CoV-2 gains entry into host cells, so the RBD portion of the spike protein has become the primary target of drug development in COVID-19.
Bamlanivimab showed at least a tenfold greater neutralization ability in cell cultures compared with other RBD-binding and ACE-blocking antibodies, according to the researchers.
Previous research has found that the spike shifts between two positions, up and down, with the up position enabling interaction with ACE and the down position allowing the virus to escape the immune system. The site bamlanivimab binds to is accessible in both the up and down configurations of the RBD, the researchers found.
“The unique ability of bamlanivimab to bind the spike protein in both the up and down position could underlie bamlanivimab’s greater neutralization potency compared to other antibodies,” explained Bo Barnhart, Ph.D., scientific director at AbCellera and a co-author of the study, in a statement.
The team further tested the antibody in monkeys. When the animals received the drug prior to infection, they experienced significant reductions in viral replication and load. The decreases were observed starting on the first day. At the lowest dose tested, virus replication was undetectable in the animals’ noses after three days and in lung tissues on the sixth day.
The preclinical study was conducted before clinical trials of bamlanivimab were initiated in June 2020. In clinical trials, the drug has shown that as a monotherapy it can cut hospitalization by 70% in high-risk patients with early COVID-19 and help prevent the disease in residents and staffers of long-term care facilities.
But the U.S. government recently stopped the distributing bamlanivimab for use on its own, citing sustained increases in coronavirus variants in the U.S. It can still be used alongside etesevimab, another antibody drug that Lilly licensed from Junshi Biosciences.
A recent Nature study by scientists at Columbia University found bamlanivimab, either by itself or in combination with etesevimab, was no longer able to neutralize the B.1.351 variant that was first detected in South Africa.
“It has always been our view that additional antibodies from Lilly and others will need to be developed to address the evolution of the virus, including emerging variants that can differ by country or even by state,” Lilly said in a statement back in mid-March. “In fact, this is what drove our work on bamlanivimab and etesevimab together and continues to underpin our strategy moving forward.”
Lilly and AbCellera have been tracking the emergence of variants and have identified a new antibody that’s predicted to neutralize all circulating variants, Falconer said. “This antibody, currently referred to as 1404, moved into preclinical development and manufacturing in January with our partner, Eli Lilly, and we are continuing to work closely with them and our collaborators for rapid advancement,” she added.