Antibody Hope in SARS-CoV-2
You may recall from our previous post that antibodies are the special proteins produced by B cells of the adaptive immune system that latch on to invading pathogens to prevent the spread of infection in the body. These large and complex proteins are important in the natural response to viruses, and more recently, scientists have started to leverage them for targeted therapeutic responses. Just imagine: if we could design and mass-produce antibodies that block a virus like SARS-CoV-2 from entering cells and replicating, we would have a very effective treatment strategy for the virus.
Of course, as with many things in science, that’s a beautiful theory, but the reality is fairly complicated. Several recent papers, however, have contributed to the growing set of potential therapeutic antibodies for SARS-CoV-2, so let’s dig into what they found and determine what hope it may bring.
Catching the spike
There have been several neutralizing antibodies against SARS-CoV-2 identified to date. (A “neutralizing” antibody is one that does not just latch on to the target virus, but latches on in such a way as to block the virus from effectively entering cells and replicating.) Most of these are antibodies that specifically bind to the virus’s Spike protein, which is the glycoprotein on the outside of the lipid envelope that allows the virus to bind to the host cells’ ACE2 receptor and get inside the cells. (We discussed this process in greater detail here.)
|Left: a virus (shown in green) binds to a receptor on the host cell, thus gaining entry. Right: antibodies (shown in blue) bind to viral proteins, blocking the virus’s ability to bind the host receptor.|
It makes sense that the Spike protein would be the most vulnerable to antibodies-- it’s on the outside of the virus, sticking out like a, well, spike, and when blocked, the virus can’t get into the cell. The handful of neutralizing antibodies that have been identified thus far from mouse models, llamas, and humans with COVID have been found in the lab to bind not just to the Spike, but specifically to the Receptor-Binding Domain (RBD) of the Spike protein, which is the portion of the protein that binds directly to host cells. These antibodies have a lot of promise: the fact that a single antibody can neutralize the virus is not a given, and the fact that we have identified several such antibodies increases the chance that we can effectively develop a therapeutic that can be mass-produced. If the virus were particularly squirrely (as, for example, Influenza and HIV are), we might not find any antibodies, or we might find we need a set of several antibodies to prevent viral replication.
Now, these antibodies have been identified as neutralizing in vitro and in animal models so far, but there are still many unknowns. For example, will a single monoclonal antibody (that is, one type of antibody with only a single variant) work for everyone, regardless of genetic background? Maybe, but more likely different individuals will see varying efficacy depending on genetics, underlying immune cell distributions, other health conditions, severity of infection, and so on. Further, rolling out even a set of antibodies all targeted at the same portion of the virus (the Spike Receptor-Binding Domain) increases the chance that the virus will develop a mutation that allows it to escape the antibody in question.
Expanding the arsenal
Given these risks, the scientific community is continuing to look for novel neutralizing antibodies that might serve as therapeutic agents against SARS-CoV-2 (that is, vaccines and/or treatments after infection). Most recently, a paper published in Science (Chi et al) identified the first neutralizing antibody targeted against a region of SARS-CoV-2 other than the Spike RBD. Researchers extracted blood from ten Chinese patients who had been infected by SARS-CoV-2 and had recovered, and found that all ten showed evidence of having antibodies against various parts of the virus, including the Spike protein and a viral capsid protein. However, of the 35 antibodies identified across the patients, only three were able to neutralize SARS-CoV-2 in cell culture. (Notably, a different set of three antibodies with only one shared member was able to neutralize pseudo-SARS-CoV-2, a lab-created analogue that has been used in a number of studies. There are multiple reasons this might be, but, regardless, it is a good indicator of the delicateness and nuance involved in setting up and drawing conclusions from scientific studies.)
The researchers next analyzed which portion of the virus the neutralizing antibodies bound to. All five antibodies (the two that worked against SARS-CoV-2, plus the two that worked against pseudo-SARS-CoV-2, plus the one that worked against both) bound to the Spike protein. However, only one of the five actually blocked the ability of the Spike protein to bind to the ACE2 receptor, indicating that the neutralizing activity of the other four was not due to explicitly blocking the virus binding to the receptor.
|The Spike of SARS-CoV-2 binds to ACE2|
Of those four, the scientists looked further into antibody 4A8, which neutralized both SARS-CoV-2 and pseudo-SARS-CoV-2, bound to the Spike protein subunit that includes the RBD, but did not specifically bind to the RBD or block receptor binding. To understand how the antibody was neutralizing the virus, the researchers used a technique called cryogenic electron microscopy to visualize the structure created by the antibody and the Spike protein, and what they found was that the antibody was binding not to the Spike RBD but to a separate region of the Spike called the N-terminal domain (NTD). The role of the NTD is not well understood, but previous research into the structure of MERS-CoV, which has a similar Spike protein, implies that the NTD may be important for allowing the Spike to change shape and thus gain entry into the host cell. Thus, the scientists here theorize that antibody 4A8 binds to the NTD of the Spike and similarly blocks cell entry by the virus by preventing the Spike from changing its conformation, even though the virus can still bind the host cell’s receptor.
Why isn’t this Over Already?
Let’s pause for a minute to marvel: we are now at the point where scientists can, within months, extract neutralizing antibodies from patient blood, identify and quantify their binding propensities, visualize the exact conformation of the antibody-protein complex, and, in so doing, discover a new potential therapeutic for treating COVID-19 in humans. Much of this wouldn’t have been possible a decade ago, much less possible within months.
But, as fun as this paper is-- we’re not there yet. A neutralizing antibody in a lab is a long way away from a usable therapeutic, and it will take many more people to take these findings through to clinical trials and usable therapeutics. Anti-viral antibody therapy is still a new field; only three antibody treatments have been approved by the FDA for treating infections, and only one of those is a viral infection. Antibody treatment for Ebola was shown to reduce mortality in clinical trials, but large-scale treatment of an infectious virus with antibodies has yet to be attempted.
Thus, the road ahead for neutralizing antibodies is fraught with peril: antibodies are large, complex proteins that can be hard to produce; we don’t have a full understanding of how a person’s underlying genetics and health affect the efficiency of antibody treatment; and antibodies are one part of a coordinated immune response, meaning therapeutic antibodies alone may not be enough to fight SARS-CoV-2 infection. Which is to say-- there is hope and promise here, but still a lot of work to do.