Researchers at Duke University, UC Berkeley, Purdue University and elsewhere have likely made a major breakthrough in the development of drugs to treat Zika virus infections. They discovered an unusual monoclonal antibody, not of the common immunoglobulin G family, but rather immunoglobulin M. This antibody is extremely potent at neutralizing the Zika virus in tissue cultures, as well as in live animal experiments.
Monoclonal antibodies are among our greatest assets in treating and preventing disease caused by viruses. While the spotlight has been entirely on monoclonal antibodies against Covid-19 during the pandemic, antibody candidates for other serious pathogens have also made strides. Here we describe a new antibody candidate that neutralizes the Zika virus, which is responsible for thousands of infections each year.
While not as widespread as the 2016 peak, documented Zika virus infections still occur in more than 80 countries, with about 18,000 cases per year. Infections are most common in areas closer to the equator, as mosquitoes are the main means of transmission of the virus.
The incubation period for Zika virus disease is between three and 14 days, after which symptomatic patients develop fever, rash, conjunctivitis, joint pain and headache for up to a week. One of the more serious complications of the Zika virus occurs in pregnant hosts. About 14% of host fetuses develop severe brain and eye abnormalities. Many cases result in stillbirth, premature birth, or miscarriage.
Researchers Singh et al. aimed at discovering a monoclonal antibody treatment to calm the virus still raging in tropical regions. The scientists were surprised to find that a specific type of antibody, immunoglobulin M (IgM), was particularly active with regard to Zika virus immunity to the fetus during pregnancy. The vast majority of antibodies are immunoglobulin G (IgG). While most antibodies are a single ‘Y’-shaped monomer, the IgM antibody presents in a set of five, or a pentamer. IgM antibodies are the largest antibody produced and are the first to respond to the first exposure to an antigen. The monomers are linked to their adjacent monomer by a disulfide bond and a linking chain keeps the large antibody intact.
Singh et al. extracted plasma IgM to test binding and neutralization of a cohort of 10 pregnant Brazilian women during the 2015-2016 Zika virus outbreak. They eventually isolated one Zika virus monoclonal antibody candidate, DH1017.IgM, which demonstrated the most robust Zika neutralizing ability in early tests.
In addition to neutralizing the parental Zika virus, DH1017.IgM also neutralized ZIKV PRVABC59 and ZIKV H/PF/2013, two prominent variants of the parental virus. DH1017.IgM also had a lower mutation rate than other antibody candidates in early tests, meaning that neutralizing ability is unlikely to change due to chance mutations in the antibody.
Singh in particular et al. discovered that the pentameric form of the IgM is crucial for the binding of DH1017. As a Fab fragment, i.e. only the arms of the ‘Y’ form, the antibody bound poorly. DH1017 bound roughly 20 times more strongly as an IgG monomer, but as an IgM pentamer, the antibody bound more than five times more strongly than the monomer. At the same time, neutralization for IgM was 40 times stronger than the IgG monomer.
The researchers conducted further tests on mouse models to determine in vitro neutralization for DH1017. They found that the IgM antibody protects against severe and fatal cases of Zika virus infection at lower doses of 50 or 100 micrograms, but protects much more effectively against viremia at higher doses. Again, the researchers found that the IgG monomer version of DH1017 fails to reach the points set by the pentameric IgM.
Singh et al. note that the five-armed IgM antibody “can contact up to five epitope pairs compared to a single epitope pair for the bivalent DH1017.IgG.” This would explain the vastly increased binding and neutralization. Imagine a chest with a single lock and a chest with five locks. Which is safer?
The researchers also found that the IgM can bind epitope pairs across different virus particles, creating a cross-linked virion epitope. Now imagine several chests chained together and locked. The IgM antibody form offers fascinating advantages over its IgG counterpart.
The DH1017 antibody, like many antibodies that treat viruses that primarily affect lower-income countries, should be produced at a low cost to ensure that those most in need of treatment can afford it. With current technologies, monoclonal antibodies can be produced at $200 and $250 per gram. DH1017 could be a godsend for those still affected by the Zika virus, especially pregnant women in low-income countries.
In a broader sense, this study opens a new avenue for the development of monoclonal antibodies. It is clear that pentameric IgM antibodies bind and neutralize much more effectively than monomeric IgG antibodies. It would be relatively easy to convert potent IgG antibodies to IgM by replacing the Fc portion of the antibody. If researchers could exploit that advantage and develop antibodies against other global antigens, such as SARS-CoV-2, the reward would be well worth it.