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Details of a New Anti-Coronovirus Neutralizing Antibody

There’s a lot of work being done on antibodies for the coronavirus and on the protein domains they recognize. This of course has bearing both on the idea of monoclonal antibody therapies and for the vaccines that are in development, so let’s have a look at the new data. For reference, here’s a background post on some of the proteins that the virus makes and the mutations that have been spotted in them, here’s my post on the basics of antibodies and immunology as relating to the epidemic, with an update here, and here’s my earlier post on monoclonal antibodies as a treatment, now updated with some new items.

So you’ll see from that last link that what we’re after are neutralizing antibodies, not ones that just bind to the coronavirus without interfering with it enough to be useful. The particular protein that everyone believes is the natural target for such things is the famous Spike, because it’s well-exposed on the surface of the viral particle and is crucial for the virus to enter human cells. In particular, the receptor-binding domain (RBD) of the Spike is the part that interacts with human ACE2 to start the viral entry process, so that’s had a huge amount of work directed toward it, much of which is very much informed by the work done on SARS and MERS (here’s a new review). In fact, some of the antibodies developed for those have been shown to cross-react with the current viral spike protein, although this is by no means a universal property.

We now also have several reports of antibodies that have been raised to such proteins – some of them isolated directly from patients, and other monoclonal ones made by techniques that are more directly amenable to protein scale-up. Obviously, the companies working in this area have such antibodies already in development, but we don’t know much about them yet. Here’s a report from a team in China that isolated monoclonal antibodies by finding memory B cells from recovered coronavirus patient blood samples. Their three best candidates all bound to the Spike protein’s receptor binding domain, but only two of them interfered with the association with human ACE2.

That might make you wonder about the third one, but here’s a new open-access paper from a Dutch team (Univ. Utrecht and Erasmus/Rotterdam) that describes an antibody like that in detail (a preprint on some of this came out back in March). They produced spike proteins from several coronavirus pathogens (the latest one, SARS, MERS) and immunized mice with them sequentially over two weeks. These weren’t just any mice, naturally – they were H2L2 animals, a trademark of Harbour Antibodies for a strain that has a partially humanized immune system. B cells from the mice (spleen and lymph) were fused with myeloma cells in the classic “hybridoma” technique that produces new immortal antibody-producing cell lines. They produced 51 different lines, and screened those to find four of them that cross-reacted with the current pathogen’s spike protein. One of those (named 47D11) neutralized viral infection of Vero cells in culture, and that one is the focus of the paper. (The chimeric antibody was modified to be fully human as it became of interest for further experiments).

This antibody does indeed bind the RBD of the Spike protein, and it binds to both the SARS coronavirus and to the current one (although it’s even more potent for the earlier variety). But there was a surprise: assays (biolayer interferometry, for the specialists) showed that the antibody did not keep the Spike protein from binding to the ACE2 protein. It did, though, stop the next stage of the viral entry process (syncytia formation, where the outer membranes of the virus and the human cell start to merge), so there’s an unknown mechanism at work here that doesn’t involve direct competition with ACE2 binding. That’s something to keep in mind – there are a lot of steps involve in viral infection, and several ways to interrupt it with an antibody. A paper last year on antibody modes of action against SARS and MERS may have some insights on how such a mechanism might work, if people want to dig into the details. But it seems clear that failing to knock down the RBD/ACE2 interaction alone is not enough to disqualify an antibody candidate.

Now, even that RBD region has subregions. It’s 168 amino acids long, and that’s a pretty good amount of real estate. There’s a core domain that contains a smaller 60-residue exposed subdomain that loops out – that’s the part that first recognizes the ACE2 human protein. That is the tip of the spear: the receptor-binding loop region poking out of the receptor-binding domain of the Spike protein of the coronavirus. The problem is, if you target that particular region (which at first sounds like something you’d want to do) you run the risk of losing activity due to mutations, because that region is one of the more variable ones in the whole Spike. This 47D11 antibody, though, binds to the core domain of the RBD, which is much less variable, and that core-domain binding mode fits in with the way that it doesn’t seem to interfere with the ACE2 recognition event. And as the authors mention, this opens up the possibility of combining this antibody with another one that binds the exposed loop as a dual-acting therapy.

Meanwhile, the Israel Institute for Biomedical Research announced, without any real detail, that they also have a neutralizing antibody. The word “breakthrough” was thrown around by Israeli officials, but I wasn’t as impressed. At this point, finding a neutralizing antibody is not really news, because most recovered patients (not all!) have recovered by generating them. What’s of interest are the details past that: where does this antibody bind, exactly, and with what affinity? What part of the viral life cycle does it disrupt? The paper from the Netherlands goes into those details (without ever actually mentioning the protein sequence of their antibody, though, as many have noticed). But the  Israeli announcement is best met with a shrug until more details are released. We can expect more announcements of this type in the near future, I would think.



39 comments on “Details of a New Anti-Coronovirus Neutralizing Antibody”

  1. MoAb says:

    The insertion of a Furin (also plasmin, trypsin, Xa) protease cleavage site in the spike glycoprotein (aa682 – aa689) is strikingly novel in SARS-CoV-2, has not been found in other related coronaviruses (so perhaps handmade by virologists, who were playing with this insert as they did earlier on other viruses) and is supposed to make the virus highly virulent. So is it a selection criterion that an antibody also protects this unique (hand made?!) Furin cleavage site?

    1. antibody guy says:

      MERS-CoV contains a furin cleavage site as well. Was this also engineered, in your opinion?

      1. Derek Lowe says:

        Exactly. There are no signs of human engineering in the virus, to the best of my knowledge.

        1. MoAb says:

          It is just strange that all the related Bat, Civit cat, Raccoon and Pangolin sequences lack the insert of 12 nucleotides creating the extra basic sequence PRRA making it more sensitive for various human proteases and mind you this is not a mutation but insertion of 12 nucleotides (presumably increasing the virulence): see (
          Where does this insert comes from? Probably not a Bat coronavirus and a Camel coronavirus (MERS) meeting each other in a Pangolin on the market in Wuhan giving a cross over SARS-Cov2. On the other hand-but certainly no evidence this happened- this insert can be rationalized and made by a molecular biologist starting for instance with a Bat sequence and some cut and paste. Better suggestions are welcome….

          1. Churlish says:

            MoAb, I’m not an expert in this area but the situation that you describe seems that it is readily accounted for by natural selection:
            1) a furin cleavage site in the spike protein makes coronaviruses more virulent in humans but not in their natural animal hosts;
            2) coronaviruses mutate rapidly and generate multiple different strains that differ in their sequences;
            3) different coronavirus strains periodically jump from animals to humans;
            4) those coronaviruses that contain a furin cleavage site are more likely to be noticed and studied as they are more transmissible and virulent in their new human hosts, while those that do not contain a furin site are more likely to fizzle out in humans and are seldom detected.

            Again, I don’t know that any of the above statements are true (particularly if the furin site is as key as described), but the explanation seems reasonable enough without invoking lurking malevolent bio-engineers.

          2. Woke says:

            It’s not a furin site, it’s a tiny 5G antenna

          3. pezo says:

            Check out this video, it claims the same as you do:


          4. mammoth says:

            There is a bat coronavirus (RmYN02) that contains a furin sequence (R-AAR-).

          5. Ab says:

            How important is the unique poly basic insert and where does it come from?

            the unique insert of 12 nucleotides creating the extra polybasic sequence PRRA makes SARS-Cov2 more sensitive for various human proteases and presumably increases the virulence:
            the unique insert in SARS-Cov2 is not a mutation and is not present in most closely related corona viruses. However, similar polybasic cleavage sites (for furin and other human proteases) are well known in numerous other viruses and its cleavage is essential for infection:
            It has been suggested that most likely the insert in SARS-Cov2 has been acquired by recombination, but it has not been indicated how and from which virus/species:
            Virologists publish for more than a decade that they engineer polybasic cleavage sites in viral genomes to enhance pathogenicity: e.g. in 2011, using recombinant technology in a lab an avirulent avian influenza virus could be converted into a highly pathogenic phenotype (with engineered polybasic cleavage site):

        2. mo says:

          • the unique extra polybasic sequence makes SARS-Cov2 more sensitive for human proteases thus increasing the virulence:
          • the unique insert is not present in most closely related corona viruses; similar polybasic cleavage sites are known in numerous other viruses and essential for infection:
          • presumably the insert has been acquired by recombination, but how and from which virus/species:
          • Virologists engineer polybasic cleavage sites in viral genomes to enhance pathogenicity: in 2011, in a lab a non-virulent avian influenza virus could be converted into a highly pathogenic virus

        3. Insert says:

          Inserting a polybasic cleavage site is possible in the lab for at least a decade. See for instance this paper: H9 avian influenza reassortant with engineered polybasic cleavage site displays a highly pathogenic phenotype in chicken: Journal of General Virology (2011), 92, 1843–1853

    2. Toni says:

      The Furine-cleavage site is supposed to be cleaved by plasmin:
      Elevated Plasmin(ogen) as a Common Risk Factor for COVID-19 Susceptibility;

      on the other hand, doctors are considering giving tPA (which cleaves plaminogen to plasmin) for fibrinolysis in particularly severely ill COVID patients.:

  2. Rob says:

    There’s a report out that the strain of the virus prevalent on the East Coast contains a mutation that makes it more contagious (and maybe more lethal?). I think the report said that the mutation was in the region that codes for the spike protein. It’s also the strain more common in Europe. Any comment?

    1. SP123 says:

      This has been addressed pretty thoroughly by scientists on Twitter, with a great deal of skepticism. All they did was identify changes in prevalence of strains containing a particular mutation and hypothesized that therefore it’s more contagious. They did not actually demonstrate that it is any more infective in any assay, that changes in prevalence were due to higher transmissibility rather than other correlative factors such as founder effects, or that it has any difference in morbidity. The headline of the LA times article and follow-ons totally oversell what the paper actually observed. I wouldn’t say the claim is wrong, but unfounded.

      1. Aleksei Besogonov says:

        I’m not a specialist in zoonotic viral diseases, but I worked a lot with evolutionary algorithms.

        So it kinda makes sense that a new virus would undergo rapid mutations making it more infectious. It’s also likely that once the initial easily accessible fitness landscape is exhausted, there would be a plateau where most mutations are deleterious.

    2. steve says:

      It was pure speculation that the mutation made the virus more contagious. You can easily also envisage a founder effect – whoever first brought the virus to Europe (Italy?) had that mutation and it happened to be the one that swept through the continent and then came to NY. A lot more work needs to be done to show the mutation confers increased infectivity or virulence.

      1. Derek Lowe says:

        This is the next blog post, as it happens. . .

  3. Halbax says:

    I think most epidemiologists are skeptical of this claim. If this particular viral strain was more contagious then it should crowd out other strains, but that isn’t what is happening. Two strains have been circulating in Washington state (one was the strain you mentioned) and both seem to be declining at the same rate.

    1. B says:

      That IS actually slowly happening, but it’s also very possible it is happening due to re-introductions from Europe and other areas where the D614G mutation is more common.

  4. steve says:

    The second step in cell entry for the virus after binding to ACE2 is cleavage by TMPRSS. Any antibody that blocks cleavage would also prevent viral entry; it would be interesting to see if the antibody bound to spike protein inhibits cleavage. That should be a simple experiment to do.

    1. Giannis says:

      Inspired by your comment I dug a little. TMPRSS2 is not essential! That means that an antibody against it could work to prevent SARS2 infection. Although I still believe that an anti-ACE2 approach should also be investigated.

  5. ADumbQuestion says:

    OK, this is an 8th grade level question, but I don’t know where else to pose it:
    Ncv-Wuhan (i like place names) has over a dozen attachment spikes. If you have an antibody that binds to the spike protein you’re unlikely to cover all of them bc there are vast numbers of virus particles. Covering even half the spikes would seem to require flooding the bloodstream with the antibody particles, I can’t imagine one’s body taking kindly to that.
    So, if the multiple assumptions above have any congruence with reality, how does binding to one or three of those spikes inactivate the virus?

    1. loupgarous says:

      “If you have an antibody that binds to the spike protein you’re unlikely to cover all of them bc there are vast numbers of virus particles. Covering even half the spikes would seem to require flooding the bloodstream with the antibody particles, I can’t imagine one’s body taking kindly to that.”

      You’ve got an implicit additional assumption there that the antibody particles in these studies cause antigenic responses by the host immune system. That uses the “old” definition of “antigen”, “a structural molecule that binds specifically to an antibody only in the form of native antigen”. Now, “antigens” can be any molecule or linear molecular fragment, after processing the native antigen, that can be recognized by a T-cell receptor.

      Monoclonal antibodies are designed to, as much as possible, to bind only to (in the case of SARS_CoV strains, at least) domains of interest on that virus in order to stop its entry into a cell for replication. I’m not absolutely sure that the antibodies described in the papers Derek mentions cause no antigenic response from the human immune system (it’s something to watch for), but it ain’t necessarily so. Other off-target actions by the monoclonal antibodies are also things to watch for, but hopefully won’t be an issue.

      1. loupgarous says:

        That comment didn’t include what happens after a monoclonal antibody binds to its intended target. That virus won’t, I think, continue to exist after being “site-blocked” by an mAB. Again, this is just a guess, but it’ll probably be tagged for ubiquitination by parts of the host immune system and sent on its merry way to be sliced and diced into virus fragments.

        1. ADumbQuestion says:

          Thx, this is interesting.

          Now, if I wanted to learn the basics of biology, using neither a dumbed-down nor graduate-level starting point, what’s a good place to start? I can’t do this on a schedule, as i’m disabled and basically a zombie about 80% of the time and I can’t predict when the other 20% is. At the some time I’d rather move more slowly through undiluted material than skate through something meant for idiots.

          1. x says:

            Try undergrad textbooks. They’re reasonably accessible and will definitely hit the fundamentals. General biology may or may not be of interest to you (do you want to learn about trees and ecological niches?) but physiology and immunology offer fantastic bang-for-buck if you’re interrested in human medicine.

            I don’t have any recommendations off the top of my head, but maybe you can do some research on what undergrad medical/human bio tracks use, or someone else will chime in.

          2. Some idiot says:

            Btw, not my field either, but I saw somewhere over the last week that Springer (a very major scientific publisher) is offering lots of its textbooks free in PDF form, available from their website. I have absolutely _zero_ idea as to which ones to go for in this area, but it could be a place to look… Happy reading!

          3. loupgarous says:

            An information-dense and reasonably-priced source of information on the structure and function of the human body is Ganong’s Review of Medical Physiology. I was introduced to it while on the physiology track of biomedical engineering and still have my copy 35 years later. Ganong’s is updated regularly and is probably on that balance between “dumbed-down” and “medical textbook” you want.

          4. loupgarous says:

            This is just me…. I find the “quick review” approach is good when you have limited time. Here’s Biology (Quick Study Academic) Lam Crds Edition . Only a quarter the cost of Ganong, but it’s a quick way to learn concepts you’ll see in this and similar blogs.

          5. DrGreen says:

            If you want a good primer in biology, there are some great undergrad textbooks out there. If you get an edition from 2-3 years ago, it’ll be cheap and nearly up-to-date. As I tell my students, the only dumb question is “why do I need to know that?” Knowledge is worth having for its own sake. And you never know when you’ll need, e.g., a grasp of basic epidemiology.

          6. ADQ says:

            Thx for the tips, I will look into them. The Springer item a great find!

        2. Radioactive Man says:

          Makes me wonder if you could turn a mAb into a Protac by tethering on a ligase-recruiting ligand. Could that work? Has anyone tried it?

  6. sgcox says:

    Avogadro’ number. If mAB concentration is 1 nM in the blood, that is 600 billion of molecules in 1 mL (if my calculations correct). Really doubt that virus load is close close but could not find any info by google.

    1. Thomas says:

      Isn’t this a matter of comparing virus size to antibody size?
      The some surface area of the virus must be covered. And if the antibodies are small enough, they can cover that area without a lot of mass.

      1. RChris Eikenberg says:

        Would this create more future advanced problems of blood clots as the system attempts to clean the blood?

  7. GZW says:

    Anyone else in the Pittsburgh area going to Derek’s lecture at the Pitt Chem department today? Really been looking forward to this, glad he wasn’t cancelled like the rest of the semester’s speakers

  8. JM says:

    What is the potential timeline from discovery to practical scaled application for monoclonal antibody treatments?

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