Researchers at Duke University, the University of California, Berkeley, and Purdue University have made what is likely to be an important breakthrough in drug development to treat Zika virus infection. We have discovered a rare monoclonal antibody of the immunoglobulin M family rather than the immunoglobulin G family. This antibody is highly potent in neutralizing Zika virus in tissue culture and live animal studies.
Monoclonal antibodies are one of our greatest assets in the treatment and prevention of virus-induced diseases. While the spotlight has been squarely on Covid-19 monoclonal antibodies throughout the pandemic, antibody candidates against other serious pathogens are also advancing. Here we describe a new antibody candidate that neutralizes the Zika virus, which causes thousands of infections each year.
Although less prevalent than it was at its peak in 2016, documented Zika virus infections still occur in more than 80 countries, with approximately 18,000 cases annually. Infection occurs most frequently near the equator, as mosquitoes are the main route of transmission of the virus.
the incubation period of Zika virus Illness lasts between 3 and 14 days, at which time symptomatic patients experience fever, rash, conjunctivitis, arthralgia, and headache for up to a week. One of the more serious complications of Zika virus is pregnant host. Approximately 14% of host fetuses develop severe brain and eye defects. It often leads to stillbirth, premature birth, or miscarriage.
Researcher Shin and others. The goal was to find a monoclonal antibody treatment to quell the virus that still rages in the tropics. Scientists were surprised to discover that a specific type of antibody, immunoglobulin M (IgM), is particularly active in immunizing the fetus against Zika virus during pregnancy. The majority of antibodies are immunoglobulin G (IgG). Most antibodies are single “Y” shaped monomers, but IgM antibodies exist in sets of five, or pentamers. IgM antibodies are the largest antibodies produced and are the first to respond to initial exposure to an antigen. Monomers are linked to adjacent monomers by disulfide bonds, and the linking chains keep the large antibody intact.
Shin and others. Plasma IgM was extracted to test binding and neutralization from a cohort of 10 pregnant Brazilian women during the 2015-2016 Zika virus outbreak. We isolated one Zika virus monoclonal antibody candidate, DH1017.IgM, that showed the most potent Zika-neutralizing ability.
In addition to neutralizing the parental Zika virus, DH1017.IgM also neutralized two prominent variants of the parental virus, ZIKV PRVABC59 and ZIKV H/PF/2013. DH1017.IgM also showed lower mutation rates than other antibody candidates in early tests. This means that the neutralizing ability is unlikely to be altered by chance mutations of the antibody.
Shin and others. found that the pentameric form of IgM is critical for DH1017 binding. Antibody binding was poor as Fab fragments implying only the ‘Y’ shaped arms. DH1017 bound him approximately 20 times stronger than the IgG monomer, but as an IgM pentamer, the antibody bound him more than 5 times stronger than the monomer. In parallel, neutralizing IgM he was 40 times more potent than IgG monomers.
Researchers conducted further tests in mouse models to determine in vitro Neutralization of DH1017. They found that low doses of 50 or 100 micrograms of IgM antibodies protected against severe and fatal cases of Zika virus infection, but higher doses protected against viremia much more efficiently. Again, researchers found that the IgG monomeric version of DH1017 was unable to achieve the mark set by pentameric IgM.
Shin and others. Note that the 5-arm IgM antibody “may contact up to 5 epitope pairs compared to the single epitope pair of the bivalent DH1017.IgG.” This explains the significantly increased binding and neutralization. Imagine a chest with 1 key and a chest with 5 keys. Which is more secure?
The researchers also found that IgM can bind to different virus particle epitope pairs, creating cross-linked virion epitopes. Imagine multiple chests chained together and locked. The IgM antibody form presents attractive advantages over its IgG counterpart.
The DH1017 antibody, like many antibodies that treat viruses that primarily affect low-income countries, was manufactured at a low cost to ensure that those most in need of treatment could afford it. Current technology can produce monoclonal antibodies for $200 and $250 per gram. DH1017 could be a godsend for people still affected by the Zika virus, especially pregnant women in low-income countries.
In a broad sense, this work opens up new avenues for monoclonal antibody development. Pentameric IgM antibodies appear to bind and neutralize much more effectively than monomeric IgG antibodies. It is relatively easy to convert a potent IgG antibody to her IgM by replacing his Fc portion of the antibody. If researchers could take advantage of that and design antibodies against other global antigens such as SARS-CoV-2, the rewards would be well worth the effort.