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Monoclonal Antibodies for the Coronavirus (Updated May 5th)

Antibodies as a therapy

Let’s have a look at what is (in my opinion) probably our best shot at a reasonably short-term targeted therapy against the COVID-19 epidemic: the possibility of using monoclonal antibodies. These can be developed more quickly than vaccines, and a lot more quickly than a new targeted small-molecule antiviral.

Like everything else, though, there are some tradeoffs, which will become apparent as we go into the details. So, a quick antibody refresher: recall that if you successfully fight off an infection (from the coronavirus or most anything else) then you have probably raised antibodies to that pathogen. I have a post here with some basics; like all of immunology, though, it’s a subject that just keeps on getting more complicated the further you go into it. As a quick example of one of those complications, it’s certainly possible to clear out an infectious agent without a big antibody response, if your broad-spectrum innate immune system is up to the job. In fact, it appears that some younger people exposed to the coronavirus might be doing just that.

But most survivors will end up with antibodies, picked from the insanely huge number of different ones that every human carries around and amplified in their bloodstream because they proved effective against the virus. These are produced by B cells that became primed during the immune response, and memory B cells can survive for decades, ready to kick up production if the same infection (or something close enough to it) shows up again. Now, some pathogens can dodge this defense: malaria parasites are famously good at it, and influenza viruses mutate theirs constantly (so the flu virus you encounter this year is never really the same as the one you ran into last year – thus the need for a yearly flu vaccine that tries to predict This Year’s Model). But there are many diseases that confer lifelong immunity, or at least many decades of it. Ideally we’d want to suddenly flip everyone’s immune system over to a full-coronavirus-seek-and-destroy state, and that, folks, is what a good vaccine could do for you.

Convalescent Plasma

In the interim, though, what about finding some antibodies from people who have been infected and who then recovered? As people have been hearing about, one thing you could do is get donated blood plasma from such people and administer it directly to a sick patient. The antibodies in the convalescent plasma should do exactly what they did in the original patient: bind to the coronavirus particles whenever they encounter them. Getting this to work on scale as a therapy has some real challenges, it should be noted, but a six-company consortium is trying to get it to work (Takeda, Biotest, CSL Behring, BPL, LFB, and Octapharma).

Neutralizing Antibodies and Not-So-Neutralizing Ones

This mechanism brings up another subtlety, though: antibodies can bind to all sorts of things and to all sorts of protein surfaces (although it’s for sure that some proteins set them off a lot more readily than others, and when you yourself have a particular one like this that you’re sensitive to, you have an allergy!) What parts of the coronavirus will they bind to, and with what effect?

The antibodies might stick on to a part of the viral particle that still leaves it operational and infectious, or they might bind in a way that shuts it down right where it stands (probably by covering up the parts, like the Spike protein, that are needed to recognize and infect human cells). Those two classes are called “binding antibodies” and “neutralizing antibodies“, and if you are offered the choice you should probably take the neutralizing ones. Your body will raise both kinds, most likely: several different antibodies will turn out to recognize a pathogen, and your immune system will expand different candidates (a polyclonal response, in the lingo). Like baking powder in biscuits, the neutralizing ones are double-acting: they shut down the virus’s function by binding to it, and at the same time alert other immune system cells to come destroy the particle they’ve latched on to. The plain binding antibodies can still do the latter job, but (as has been mentioned here and many other places), they can also have an extremely unwanted effect, antibody-dependent enhancement, where their binding to the virus actually makes it easier for it to infect human cells. It’s been documented in the closely related MERS coronavirus and many others. You want to avoid that at all costs; safer to go with the neutralizing ones.

A Temporary Vaccine?

You would certainly imagine giving such neutralizing antibodies to people who are sick with the coronavirus, of course. But a particularly interesting possibility is giving them to people who aren’t infected yet, as a preventative. If the antibodies are potent enough and long-lasting enough in circulation, they could provide sufficient protection for weeks or possibly up to several months (and this would take effect immediately upon injection, as opposed to the immunological time lag seen in vaccination). This will take some hard work and close observation to realize, and there could well be variability in the patient population that you’re dosing (i.e., some people might lose such protection faster than others). But until a reliable vaccine is deployed, it’s a very appealing idea – and if the various vaccine efforts underway run into trouble, it might be our only option for a while.

The behavior of mAbs once they get into the bloodstream is an interesting subject if you’re into pharmacokinetics. Antibodies in general are supposed to circulate for quite a while – they’re too large to be filtered out by the kidneys, and the liver doesn’t break them down. One way they can get eliminated is by binding to the surface of a cell and getting taken in by endocytosis and broken down by lysosomes. If you’re giving an antibody to some cell receptor, that’s naturally going to be a slow but steady means of disposal (target-mediated drug disposition or TMDD). And an antibody to a pathogen like the coronavirus will be depleted in the same way as it binds to its target – how much it goes down and how much protection will be left afterwards are things that I’m just not sure anyone knows yet. There’s another effect that you have to watch out for: anti-therapeutic antibodies (ATA), which are – yep – antibodies that get raised against the antibodies you’ve giving to the patient, should they get recognized as foreign substances. That, naturally, can increase over time and with repeated exposure.

Monoclonal antibodies

Convalescent plasma has the whole suite of a person’s antibodies in it, of course. Some of them are neutralizing, some of them aren’t, and a bunch more are antibodies to all sorts of things that the donor might have encountered during their life so far, mixed in with the usual heap of random antibodies that just wander around for years looking for something to bind to. What, though, if you could reach in and select out the ones that are just what you want, and only administer those? Now we have (at last) climbed up to the topic of monoclonal antibodies (mAbs): one lineage only, hand-picked. So how do you find these things, and how do you scale them up to be real-world therapies?

Both those questions have had massive amounts of money and brainpower thrown at them even before this epidemic, which is very good news indeed. If you look at the list of best-selling drugs in the US these days, you will see the list is well-stocked with mAbs. Back when I started in the industry, these things were just barely moving out of the fairly-crazy-idea category. The first mAb approved as a drug (1986, for kidney transplant rejection) was a mouse antibody, which is not ideal. Technology improved, first to make chimeric part-mouse-part-human antibodies like Rituxumab (approved in 1997, and a big success), and then to make fully human ones (adalimumab was the first of those approved, in 1997).

Now in these coronavirus days, there’s a huge push to apply the mAb current technologies (here’s an excellent article at Technology Review about this).  There are several platforms used now, and I’ll go through some of the major ones individually:

Regeneron: For example, Regeneron (in Tarrytown, NY) has what they call their “Velocimab” technique, which as I understand it basically uses mice that have been engineered to have a humanized immune system. Exposing these animals to a pathogen or antigen of interest (multiple times) gives you human or nearly human antibodies without having to find recovered human patients to extract them from. As that article details, this technique worked to produce a mAb therapy against the Ebola virus, which really helped change the course of the epidemic. Regeneron is heading towards trials with a combination of their two best antibodies, and working to increase production (more on that issue below).

Update, 5/5: Regeneron’s CEO says that they are planning to dose their lead mAb cocktail in humans in June. They’re planning 3 trial strategies: for prophylaxis in people who haven’t been exposed, in mild patients to see if this can keep them out of hospital care, and in more severe cases as well.

AbCellera/Lilly: Then you have AbCellera, a Vancouver company that has a technique for isolating individual B cells from patient plasma into single nanofluidic compartments. The cells continue to produce antibodies inside these things, to levels that can then be used for assays. They claim to be able to run through huge numbers of candidates very quickly, and Eli Lilly is convinced. They’ve signed a development deal with AbCellera and have narrowed the company’s list of antibody candidates still further. Lilly’s CEO stated in their recent earnings call that the current top candidate shows “potent neutralization” of the virus, and that it’s now being scaled up in GMP manufacturing for clinical trials. They plan to file an IND in May and go into human patients in June. Meanwhile AbCellera is continuing to screen patient plasma samples for more candidates.

Update, 5/5: Lilly is hedging their bets, signing a development deal with Shanghai’s Junshi  Biosciencesin China for rights to their JS-016 antibody outside China.

Vir/GSK: Vir Biotechnology (San Francisco) has been working with Biogen, among others, and in April they signed a big development deal with GlaxoSmithKline, one that also involves GSK’s vaccine efforts. They have two antibody candidates from what I can see (VIR-7831 and VIR-7832), and they seem to be bringing a couple of variations to the field that could help with the “temporary vaccine” approach. I believe that one of these is selected to be particularly long-lasting in the bloodstream, while another has been chosen because of its ability to set off a notably robust and long-lasting immune response. They’ve also signed a deal with Samsung Biologics for scale-up starting this fall.

AstraZeneca: AZ also has expertise in developing therapeutic antibodies, and they’ve announced that they’re working in the area. Among their antibody sources are candidates from the Vanderbilt Vaccine Center. That got some headlines because VU listed one of their sources of funding for the effort as Dolly Parton, who has indeed made some large donations to the university over the years, and this work in particular. AZ is working with the Pandemic Prevention Platform (P3) at DARPA (as is AbCellera, above), which is hoping that sufficiently long-lasting and potent neutralizing antibodies could be given preventatively, as mentioned earlier in this post.

Amgen/Adaptive: Amgen has a huge amount of expertise in the antibody field, and in April they signed an agreement with Adaptive Biotechnologies (in Seattle) for work on the coronavirus. Adaptive has also said that they’re hoping to develop preventative antibodies. From what I can see, though, there have been no recent announcements, so it will be interesting to see what’s happening when details finally surface.

Manufacturing mAbs

Like any other large proteins, you would rather have cells make these things for you than synthesize them yourself. The Nobel-winning breakthrough, many years ago, was the idea of fusing a plasma cell (the immune cells that are the actual source of antibody production) with a tumor cell to make a “hybridoma” immortal antibody-producer line. You can do it in several other kinds of cells as well, if you engineer the sequence in as you do for protein production in general. Like any cell-culture production system, this has to be watched carefully. You want to make sure that the production levels stay within range (if it drops, that’s a sign of trouble, such as some sort of infection in your bioreactor), and that the impurity profile is pretty constant (so that your carefully-optimized purification procedures give you the same product every time), and so on. Obviously, these problems are solvable and are solved every time a new monoclonal antibody is brought to market, but they are each their own problem and need careful optimization. You’ll notice that the companies working in this area are all already thinking about manufacturing and scale-up, as well they should. Clearly we’re going to end up with a “good enough” process with rapid deployment rather than something that’s been as tuned-up as the existing mAb production lines. But that might well be good enough indeed!

Update, 5/5: Here’s a good roundup at Science of various players in this area.

66 comments on “Monoclonal Antibodies for the Coronavirus (Updated May 5th)”

  1. MAEngineer says:

    Great post as always, Derek! Some things to consider on the “Manufacturing Abs” section: most mAb production at large scale takes place in Chinese hamster ovary (CHO) cell lines containing stably integrated DNA encoding the mAb of interest (some other cell lines, too, from what I gather; I’m not that kind of an engineer, though). Cell line identification and engineering is likely to be important for maximizing the rate of production of anti-SARS-CoV-2 antibodies. The scale of production we’ll need if one of these antibodies gets approved before a vaccine could be orders of magnitude bigger than current mAb production pipelines can support.

    1. Derek Lowe says:

      Thanks – I added a bridging sentence in there after the hybridomas. I figure that I’ll eventually do a whole separate post on production of mAbs, and use this one as the reference post when I do.

      1. Giannis says:

        Let’s say we got lucky and Regeneron found an antibody that inhibits SARS-CoV-2 with low lopicomolar inhibitory concentration. Do we have any idea what dose will be required? 10 mg? 100mg? 500mg?

    2. Dr. Augustine says:

      I know about the Chinese hamsters uses since 1948 when a doctor managed to sneak a whole crate out of China, I’m thank full of that because I’m a living example of defeating NHL
      CD 30 tumor cancer v& I was only given 2 infusions
      One month apart @ 130 mil. Each multiple tumors practically disappeared overnight, but I’m a researcher as well & found a different way to deactivate all Viruses but nobody seems to care, no body believes me.

      1. loupgarous says:

        You lost us at “deactivate all Viruses”.

    3. Victor Rutledge says:

      I’m curious as to the possibility of hybridoma producing something unforeseen. Cytokines are a large group of proteins, and a single miscalculation can lead to a Cytokine-release syndrome or reaction. In addition, the high speed method of production could cause an undesired protein attachment, or some DNA modification not originally intended. (No jokes about ‘zombie disease’, please) Since some of these alterations can be hereditary, we could alter the DNA of humanity, without intending to do so, and in such a way that it might not appear for generations. Conversely, it could happen like a CRISPER event, suddenly and with anaphylaxis concurrent. It’s a dangerous game, even though the rewards are life, instead of death. Not a good place to be, in terms of choices.

  2. “is is Abcellera” should be “as is Abcellera”

  3. Luysii says:

    These are all great posts — detailed analysis of the state of play for a variety of therapies for the virus. What do Derek and the readership think of the variety of social therapies currently being implemented for the virus? The ‘therapies’ vary from degrees of increasing lockdown, keep it the same and degrees of decreasing lockdown. They are about to be implemented all over the country.

    It’s time to place your bets gentlemen. What do you think their effect will be — no change/increase/decrease in new cases, positivity rate for the genome, positivity rate for antibodies. While no two situations are exactly the same, it’s as close to a controlled study as we’re likely to ever have.

    No retrospective looking back with current knowledge saying you’d have done something different.. What does the readership think will happen at a time when none of us knows? Time to use that intellect of yours to predict the future.

    My own guess is not much, since there are so many people out there with antibodies to the virus who have never been sick.

    What’s yours?

    1. Druid says:

      We have been “educated” about the importance of R0 but not much thought or explanation has been given to its principal components. One is the intrinsic transmissability of the virus. How much is shed; which routes are efficient (eyes, nose, mouth?); once on the mucosa, what load is infective; what proportion of non-immune people succumb; how long does it survive in infectious form (not just the RNA) on surfaces; how easily it is it destroyed; will we get immunity? Remember those discussions about fogging the streets? Not many of these things are known, but the track and trace specialists look for 15 minutes of contact. which is something to go on.
      Then there are the behaviours, chief of which is the number of people an infectious person spends 15 minutes with before ceasing to be infectious. There are suggestions that infected people are infectious before they are symptomatic and then for only a few days afterwards, so let us suppose a victim is infectious for a week, half of that unaware. Then some victims will take to their beds while others will cough their way on the train or bus to work, shopping or leisure where they cough some more. In a week, how many people are you close to for 15 minutes?
      The models look at the consensus – a sort of average – of behaviours, whereas we may suspect that a few superspreaders outweigh the thoughful types. As an individual, I could drive my personal R0 down from 0.1 to 0 and make neglible difference. Someone living in isolation in the hills does not need to change. The nerd in his bedroom playing on-line games does not need to do anything different. But if the sociable one who goes to the pub, restaurant, cafe, football match, party, wedding, concert, theater and conference does not change his behaviour, the epidemic will carry on for a long time. And in my opinion the same goes for international travel – just far too much of it to avoid pandemics. Meanwhile we all must suffer the lockdown. But when we feel it is safe to go out again, is anyone up for a 1500+ delegate international conference, where we shout at each other over the coffee cups?
      There is a lot of talk about lost-liberties and potential discrimination as well as the nose-diving economies, but how else will we adapt to the new reality? Maybe queuing 2 meters apart outside the shop to keep down the numbers inside will stay with us.There is a lot of faith in medicinal solutions on the pages, but pandemics are notoriously difficult to eradicate.

      1. loupgarous says:

        Working from home’s largely considered a perk. Even at enlightened places like Eli Lilly, where contract analysts have it dangled over their heads by team leaders who delight in abusive game-playing with their co-workers. When even pharmaceutical firms themselves tolerate that behavior, the rest of the business world won’t behave any better, and will act as Petri dishes for the next pandemic.

  4. Neal Zondlo says:

    What about nanobody approaches? Multiple groups have developed anti-spike protein nanobodies, and at least one company is involved. Considering production time and ability to do scaleup (E. coli expression!), nanobody production should have considerable advantages over mAbs. While they can have clearance issues, these are potentially manageable in a hospital setting via infusion.

    1. Derek Lowe says:

      I like nanobodies a lot, but there is the clearance issue, which would hurt with the prophylactic treatment idea. The fact that the FDA approved the first human-therapy nanobody last year does help, though: https://link.springer.com/article/10.1007/s40259-019-00392-z

      1. Giannis says:

        Adding cholesterol or something similar should massively increase the half life of nanobodies. That trick is being used for new generation of HIV fusion inhibitors. The advantage of nanobodies is that they can be produced in E.coli so we can create tons of it in a few weeks. Also they could be used for accute infections when we can just do an IV infusion to the patients in hospital, while mabs can be used as preventatives.

        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667053/

      2. Kent Matlack says:

        Are nanobodies more prone to be recognized as being foreign and generating an immune response against themselves?

        1. Giannis says:

          Depends on the nanobody scaffold. If they are humanized then it is unlikely that anti-drug antibodies will be produced in a relevant time frame.

  5. Crni says:

    As an undergrad 20 years ago I learned about yeast (or was it some other cells?) producing proteins via plasmid vectors. Now this may sound naive, but couldn’t one sequence the antibody, translate that back into DNA (yay, software!), make a plasmid, get it into yeast, get the yeast to multiply like crazy (exponentially) and produce a metric assload of the antibody? Maybe a post about that for us non-biochemists?

    1. Derek Lowe says:

      Yeast can indeed be a platform for protein production – sometimes there are problems with post-translational modifications that a particular product needs, though, and since glycosylation is really important with antibodies, they’re generally raised in mammalian cells (often humanized as much as possible).

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6027275/

      1. loupgarous says:

        There was a flurry of activity back in the 80s (I think) about genmodding goats to produce useful proteins (silk among them) in their milk. Goats, I think, because they give more milk per unit mass than cattle.

        If you can stimulate nanny goats to make colostrum more than just the immediate post-partum period, that’s a relatively rich source of useful antibodies. Feedstock would be whatever goats eat, enriched to meet the added nutritional requirements of a lactating nanny goat.

        Has anyone really looked at the feasibility of scaling up antibody production in goats? Calbiochem, if I recall correctly, used goats to make gamma globulin and related things at their La Jolla plant.

        1. loupgarous says:

          Going from goats to sheep, there’s this 2008 paper “A Proline-Rich Polypeptide From Ovine Colostrum: Colostrinin With Immunomodulatory Activity” which describes work on

          “a proline-rich polypeptide (PRP), later called colostrinin (CLN), was originally found as a fraction accompanying sheep colostral immunoglobulins. Extensive in vitro and in vivo studies in mice revealed its interesting T cell-tropic activities. The polypeptide promoted T cell maturation from early thymic precursors that acquired the phenotype and function of mature, helper cells; on the other hand, it also affected the phenotype and function of mature T cells. In particular, PRP was shown to recruit suppressor T cells in a model of T cell-independent humoral immune response and suppressed autoimmune hemolytic anemia in New Zealand Black mice. Subsequent in vitro studies in the human model revealed that CLN regulated mitogen-induced cytokine production in whole blood cultures.”

          Are there PRPs that have been developed in the 10 years since there that would be useful in down-modulating cytokine storm?

  6. Calvin says:

    I admire Derek’s reserve on not also brining up that this was also the place where the tobacco industry thought it could make a useful contribution (useful, tobacco and respiratory disease not often being something that you can have in the same sentence). I might add that the tobacco plant is a fascinating producer of mabs. ZMapp, the initial antibody (a cocktail of three in fact) for Ebola was very very interesting and does seem to work (albeit not as well as the Regeneron or Vir ones). The really fascinating part is that you can get some really unique glycoslation patterns onto tobacco derived mabs which are immensely hard to generate otherwise (all of these companies above were involved in an effort to transfer ZMapp to CHO cells and all I recall it was incredibly difficult because one of the antibodies in particular had a very unusual gylcoslyation pattern). So maybe tobacco (plants) will, against all odds, save the human race.

    Let’s just hope that these mabs are better than most of the RSV mabs……

  7. Christophe Verlinde says:

    Very clear post, Derek. But what about the elephant in the room, the cost of the monoclonal antibodies (mAB)? Current mABs on the market are not cheap. For example in the USA 10 mL of rituximab costs about $1,000 before reimbursement. Obviously, injecting the entire population of the country would be very expensive. Instead, I could imagine giving it to selected populations: front line health care providers, the elderly, … I am curious to hear the opinion of the readership.

    1. Derek Lowe says:

      Yeah, I haven’t addressed cost for any of the therapies that I’ve written about, to be honest. My guess is that a really useful mAb will be given to health care workers and other first responders, then people whose work unavoidably brings them into contact with people. Keeping those parts of the economy going would seem to be a good use of some public funds?

    2. Ilya Yasny says:

      According to my latest research last year the cost of goods per 1 gram of mAb is now less than $35.

      1. Tony Nonose says:

        $35 for the raw materials, perhaps, but a little bit more for the multimillion pound manufacturing facilities and teams of biochemical engineers?

        1. Giannis says:

          No. This is the price that you get if you make a phonecall to a big producer of mabs in China or India. You just need to order a lot of it to get a price under $100. The CHO strains that they have are producing 10 grams per liter which is insane.

          1. Tom says:

            Isn’t the high cost of therapeutic antibodies is largely due to the extensive purification steps, which can be missed when preparing monoclonals for research purposes? This would help explain why we still see such high prices for biosimilars in comparison to generics.

          2. Mammalian scale-up person says:

            Reply to Tom: Correct, the $35 stuff is not cGMP compliant, usually not even sterile, has not been rigorously purified or virus filtered or formulated for specific stability & dosing parameters. It has not been checked for sequence confirmation or posttranslational modifications.

    3. Alan Goldhammer says:

      the mark up on the approved mAbs is quite high and we don’t know how much. Price increases have been much higher on a year to year basis than for most other drugs. Let’s say for sake of argument that the government can come in and be a big purchaser of these drugs and that an autoinjectable formulation can be made. You want to give this to everyone over 35 as an arbitrary cut off (younger than 35 get very mild symptoms) and this is about 1/2 of 330M which means 165M need to get this. The government negotiates a price of $750/month/person you end up with a total price tag for one month of about $120B. Now you might think this is a huge number but the economists I’ve read say we are losing $85B every week that things are shut down under the present conditions. You see that the $120B expenditure now seems pretty reasonable based on monthly savings.

      The other thing we don’t know is whether humans on mAb therapy would still generate an immune response with subsequent infection. If so, the mAb prophylaxis might not be needed for more than a few months. Of course this is all conjecture based on an ideal case.

      1. Charles H. says:

        “Younger that 35 get very mild symptoms” may be overly optimistic. Recently there has been a syndrome in children that may be related to COVID. (It’s hard to see why else it would show up just now.) Some kids have died of it.

        There are also worries that the blood clots could do permanent damage, and not only in the lungs. Most of the studies just consider “Did the survive”, which is the clearest endpoint, but it’s not the only one.

      2. nobody says:

        With $85B a week economic losses from the COVID-19 shutdown, any government which treat intellectual property as an inviolable right and tries to negotiate with the drug industry over a treatment or vaccine will have its head handed to it. Government buyers will have have very little leeway to refuse any price the industry demands because the cost of refusal is the implosion of the economy and millions of dead.

        There is a very real risk that very large portions of global GDP will be looted into the pockets of industry shareholders unless governments are willing to dictate terms to industry (e.g. production cost + %2.5, or your executives go to prison) or seize and nationalize production.

        Free markets are not a suicide pact.

        1. metaphysician says:

          “Production cost + 2.5%” wouldn’t be enough to convince a pharma company to not just shut down, not unless you define ‘production cost’ to include *ALL* the actual costs of research and development. R&D is not free, and people should stop pretending it is.

    4. Susan Holbeck says:

      My dog gets a monthly monoclonal antibody injection (Cytopoint) and the cost is just over $100 per month.

    5. Ezra Abrams says:

      20 years ago, a scientist involved with therapeutic oligos (think Hybridon) told me the cost to produce a gram of therapeutic grade oligo

      I don’t recall the exact number but do recall my jaw dropping at how low it was (at the time a single PCR primer was 250$, now IDT Is so cheap if I can’t find it in the -20, I just order a new one, cheaper then looking)

      The point is, when you have decades of optimization and scale, costs drop

      My Fav: A toyota camry runs for 10 years, in hot and cold, over rough roads, and just needs service. It costs less then most scientific instruments which run a few hours a day in a controlled lab

      1. metaphysician says:

        A Toyota Camry is also about a million times less precise, and produced with much greater efficiency of scale. A reasonable person wouldn’t expect it to cost the same as a precision scientific instrument.

        Or to put it another way: would you trust your life to, say, an HIV test that is as accurate and reliable as the Check Engine light on your car?

        1. fajensen says:

          Maybe. But, I would have to change the bulb first 🙂

  8. RespDoc says:

    There is the issue of PK. The site of virus infection is apical border of respiratory epithelium which is not accessible to large MW Mab which is restricted to the plasma compartment. Neutralising antibodies inhibit viral entry ……so main role would be in preventing systemic extra pulmonary infection (renal, cardiac, brain) in the critical care situation. If used early might prevent cytokine storm……

    1. Ilya Yasny says:

      How do natural antibodies penetrate the epithelial barrier then?

      1. Giannis says:

        FcRn is expressed in some epithelia.

        https://www.ncbi.nlm.nih.gov/pubmed/26634928

      2. johnnyboy says:

        In order to be truly preventative (ie. prevent the initial respiratory tract infection), you would have to give an IgA, which has a secretory component allowing it to migrate into the mucociliary lining, and thus inactivate viruses *before* they get to the mucosal epithelial cells. There is probably some IgG as well in the mucociliary layer, but I believe the bulk of respiratory immunity is mediated by IgA. If you give an IgG by subQ or IV injection, it will remain largely in the circulation rather than migrate to mucosal surfaces. So it will likely be more for prevention of the systemic invasion by the virus (ie. the more severe phase), but might not stop the initial replication cycles in the respiratory tract mucosa.

        1. Barry says:

          Work with RSV showed that mucosal (IgA) response may not be tightly coupled to humoral (IgG) response? Measuring IgG in blood may not tell the tale for Covid19, either

          “Resistance to challenge correlated with neutralizing antibody
          titres in nasal secretions and to a lesser extent in serum.”
          Determinants of susceptibility tochallenge and the antibody responseof adult volunteers given experimentalrespiratory syncytlal virus vaccinesP.J. Watt*, B.S. Robinson*, C.R. Pringle t and D.A.J. TyrrelFThe virulence and immunogenicity of a wild-type respiratory syncytial (RS) virus together withfour temperature sensitive (ts) mutants derived from this isolate were tested by intranasalinoculation into adult volunteers. Resistance to challenge correlated with neutralizing antibodytitres in nasal secretions and to a lesser extent in serum. All ts mutants were reduced in virulence.Mutant tsl B caused mild or asymptomatic infections yet induced antibody responses comparablewith wild-type RS virus. Tsl B might be developed further to produce a live-virus vaccine.Keywords: Respiratory syncytial virus; antibody responsesIntroductionRespiratory syncytial (RS) virus is the major respiratorypathogen of infancy and early childhood. Infection withRS virus is disseminated via large droplets or by directinoculation into the nose or eye. Annual outbreaks occurin the winter or the rainy season in both temperate andtropical countries so that few infants escape infection bythe age of 2 years. During the primary attack RS viruscauses lower respiratory tract disease in some 40% ofinfants 1. Such life-threatening infections are unusual inthe first 4 weeks of life and are rare or delayed in thoseinfants with the highest cord blood titres of neutralizingantibodies 2. One implication is that maternal antibodiesmust exceed critical concentrations in order to protectthe lower airways.
          Chanock and colleagues pioneered research on alum-precipitated formol inactivated RS virus vaccine. This
          vaccine induced high sero-conversion rates but onsubsequent exposure to natural infection not only failedto protect but, in some children, induced markedlyenhanced disease 3. Subsequent work demonstrated thatvaccination induced low-titres of neutralizing antibodiesbut high levels of non-protective antibodies which couldreact with the virus to cause immunologically-mediateddisease’*. Experimental live vaccines have also beendesigned. Parenteral immunization with wild-type RSvirus proved ineffective; although some vaccinatedchildren produced antibody responses there was noprotection on exposure to natural disease 5. Intranasalvaccination was tried as the virus might replicate betterand induce local as well as systemic immunity. Certain
          temperature sensitive (ts) mutant vaccines proved satis-factory in adult trials but induced fever and ear infection
          * Department of Microbiology, Southampton University MedicalSchool, Southampton General Hospital, Southampton, UK.t Biological Sciences Department, University of Warwick,Coventry, UK. tMRC Common Cold Unit, Harvard Hospital,Salisbury, UK. (Received 14 August 1989; accepted26 September 1989)

    2. iainS says:

      I saw this related recent publication regarding lung defense.
      https://draganprimorac.org/fighting-covid-19-with-water/?fbclid=IwAR1nztXek3XKccej6zvZKFcEUCqDWUtfU8Bp-6uHJtp8lpLeOcLwVLDRqx0

      I havn’t seen it published as a formal paper yet.

    3. Joe P says:

      If this is true, how does the antibody to RSV (pavilizumab) exert its effect? RSV enters the epithelial cells the same way, and yet this treatment is effective.

      1. johnnyboy says:

        Pavilizumab reduces the risk of hospitalisation due to RSV in high-risk infants by about 50%. Whether this constitutes an effective treatment depends on your interpretation of ‘effective’. You’d need to have very rosy glasses to say that this is a very good preventative.

        1. Giannis says:

          MEDI8897 works much better. It prevents 80% of hospitalizations with a single 50mg injection. Pavilizumab simply is not a good antibody.

          https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6808696/pdf/ofz359.060.pdf

    4. Rob says:

      What about RSV monoclonal antibodies? How do they work then?

      1. Calvin says:

        Great question. Paluvizimab is only moderately efficacious in kids. It has never shown efficacy when given at massive doses in adults. All the follow up antibodies have failed (multiple P3 failures). Some in the field believe that paluvizimab has some off target effects on the immune system that are beneficial.

        This is one of the reasons I remain very nervous that most of these vaccines and mabs will raise an immune response but will do nothing clinically to help the disease.

        1. Giannis says:

          MEDI8897 works much better. It prevents 80% of hospitalizations with a single 50mg injection. Pavilizumab simply is not a good antibody.

          https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6808696/pdf/ofz359.060.pdf

          1. eub says:

            Can we confidently say that’s because we’re learned better (in a way that generalizes to a whole new virus), or is there a significant element of luck, i.e. things we don’t understand?

            It’s good that an effective example exists, but if we needed to telescope the whole long march of anti-RSV mAb research into a year or so, we’d better be taking a lot of shots on the goal in hope that one goes in.

    5. Barry says:

      As we learn ever more about extra-pulmonary damage from this virus, a monoclonal IgG may prove important in non-lung tissues. But it won’t access the eye, or the brain, or the testes, and it won’t reach the lung surface.
      What does anyone know about making monoclonal IgA? It’s IgA (and IgE) that do the work on the aveoli, on the bronchi, in the sinuses

  9. Derek, adalimumab was the first FDA-approved fully human antibody.
    Approved Dec. 31, 2002, for the treatment of rheumatoid arthritis.

  10. eub says:

    “I believe that one of these is selected to be particularly long-lasting in the bloodstream, while another has been chosen because of its ability to set off a notably robust and long-lasting immune response.”

    This pulled me up — what kind of setting-off of an immune response here? Generally with mAbs we’re talking about them *being* an ancillary immune response, floating around binding targets until all the dose gets cleared one way or another. But you already coving “long-lasting in the bloodstream” so this “long-lasting immune response” is doing what with the immune system?

  11. steve says:

    The issue with monoclonals will be manufacturing and scaleup to the levels needed. Like antivirals, these will be more effective early on when it’s the viremia that’s the primary concern rather than that over-exuberant inflammatory response. However, that means you’ll need more product in order to treat that many patients. Good for the companies but it will take longer to get production to that level. An antiviral oral drug like remdesivir or famotidine would be much quicker to scale up but will require daily dosing whereas a monoclonal could be a single dose given the extended PK of antibodies.

    1. Mammalian scale-up person says:

      Yes, long lead equipment would be problematic. Looking at about 2 years from the moment you call the bioreactor fabrication guys with a PO (if you have a building to put equipment in at all – it can’t exactly go in a warehouse), and hopefully there’s enough clean welding guys and HVAC installers to install quickly. One facility can churn out anywhere from 5,000,000 – 20,000,000 doses per year depending on the dosing regimen, mostly due to takt time limitations on logistics – it’s hard to move around that much volume of the raw materials. So would need to operate multiple facilities in parallel, and there’s just not that much capacity in the whole world – we need to keep making Herceptin and Enbrel and Keytruda too. And then there’s the question of, what are you going to make in the facilities after this particular disease has been vanquished? We usually build a facility with the notion that it’s going to have a 15+ year amortization and 10-year production runs, but if a vaccine comes along in even 5 years to make your massive capacity obsolete, then what? It’s worth it to use up any excess capacity and maybe build a couple of facilities on a platform that can be easily repurposed, not more.

      Even in terms of operation: if this is a very good cell line that only eats RPMI and we’re purifying with ProA + orthogonal IEX membrane chrom, we’re still going to have raw materials limitations in production. Trace elements and weird amino acid cocktails just aren’t manufactured in that many places, and those places are affected by the disease too.

      1. ezra abrams says:

        +100

        Your post points to the need for leadership from the POTUS, which in this case is, I think: build the darn thing; we can cut it up for scrap if we don’t use it

        also
        I am so sick of people (ahem, economists, political scientists) offering their opinions on how fast we can manufacture/scale up for anything from ventilators to mAbs

        esp vaccines; we inject a million kids with a bad vaccine, never mind the side effects the bad publicity will set the entire field back 20 years

        1. Mammalian scale-up person says:

          Thanks. That 2 years time is resting on some pretty hefty assumptions about leveraging pre-existing design, as one of my colleagues says “if, if, if” – and there are a LOT of ways the government could help:

          Requisitioning land (they already own plenty of sites, could we use those?) for the build-out to avoid the sometimes years-long permit-wrangling and assist in site selection evaluation to avoid seismic or logistical issues. It’d be a heck of a thing to build a new site on the Gulf Coast and watch it go out of commission in hurricane season, yet I know companies that have done just that.

          Supporting utility and waste management issues – local water authorities aren’t usually prepared for the kind of demand a biotech commercial site inflicts, and struggle to get a handle on it. The nodes supporting the power grid in any given area are another concern – how much backup generator capacity will be needed? If we know someone (like, oh, some central authority) who can point to a good spot with more supporting power nodes, or even maybe build additional nodes by fiat instead of waiting for the local utility company to get their act together, that’d be a big help.

          Provide support for logistics – those big concrete slabs for prefabricated buildings don’t move themselves, but also we need roads and/or trains that can quickly move both raw materials and finished product with cold storage warehouses and distribution networks. And no, that does not mean go through a years-long competitive bidding process where the most connected mafioso gets to pour half the concrete for twice the price – I mean, get the Army Corps of Engineers to pour the concrete, because you can order it done yesterday with a Sharpie marker.

          Train new piping installation and welders. We run out of competent TIG welders and people who can read engineering diagrams just when the facility down the road is expanding at the same time – can we train the National Guard folks to do welding?

          Training for new technicians – ramp-up training is the source of many migraines – could AmeriCorps or Job Corps type programs be used to support this?

          Get rid of tariffs on steel products from overseas. Prices of heavy manufacturing equipment went through the roof last year due to Trump’s tariffs! US foundries haven’t had that kind of capacity since the 1980s and we need equipment from China, Japan and Germany.

          Use the Defense Production Act to get more raw materials, especially for plastics manufacturers – I can get more batches per year out of a facility that’s at least half single use and membrane chrom, but there will be a supply chain bottleneck because all those plastics need to be manufactured and assembled in clean rooms and we’ll need air handlers and HEPA filters to ramp up production of those. There’s polymer manufacturers in the Midwest and oil refineries in the South with ethylene / propylene production stacks that can expand production, if they have a compelling reason to do so.

          Can we set BARDA to work figuring out solids management for raw materials and logistics? It’s one of our most annoying bottlenecks due to needing a human to weigh out 54.2 kg of potassium phosphate monobasic and 203.6 kg of sodium phosphate dibasic and 400.6 kg of something else precisely, and even when we’re having them make up concentrates that are formulated with liquid handling machines it still takes a lot of manpower to make the concentrates and store them in a way that doesn’t corrode the heck out of the storage tank and piping. We’ve tried robots but for precise solids handling that we need (often of very clumpy, sticky or toxic stuff) it’s just not great, and it’s such a very boring thing that nobody wants to work on it. Some metallurgy work to get piping connections that don’t corrode in the presence of 5M NaCl and can be welded to stainless steel would be a help, too. While US foundries don’t have capacity for large equipment orders, they can definitely do weird little specialist things like making welding rings for sticking together odd customized metals.

          1. loupgarous says:

            Zooming in on the “corrosion-resistant steels” part of your post, Pakistan’s got at least one big steel mill which makes maraging steels, because you need them to handle uranium hexafluoride and other fluorine compounds, and they’ve got enrichment cascades. Perhaps Iran has the same steel production capacity. I’m assuming steels that’ll contain highly fluorinated compounds will also handle your reagents/feedstocks – but I could be way wrong.

            If the Iranians and Pakistanis need our help on ventilators, et cetera, horse trading might happen in which they make their surplus stocks/capacity of maraging steels available to us in exchange for easing sanctions to make medical supplies more available to them (in Iran’s case) and sharing our excess stocks of things they need to meet medical requirements..

          2. loupgarous says:

            Speaking to “can we train the National Guard folks to do welding?” is it possible to ask the Pentagon’s National Guard Bureau to have State National Guards comb their personnel records for members who are already trained welders? Here in the Gulf South and other petrochemically active regions, I’m sure you’d find a good many men and women in the Air and Army National Guard who’d fit your needs.

            Mississippi Gulf Coast Community College partners with local petrochemical industries to train welders, training them to meet local industries’ needs. I’m sure it’s just one of many local community colleges which work to supply specially-trained labor “just in time” for local industries. Just putting that out there.

          3. loupgarous says:

            I have second thoughts about my answer to

            “We run out of competent TIG welders and people who can read engineering diagrams just when the facility down the road is expanding at the same time – can we train the National Guard folks to do welding?”

            I lost a son to what Rumsfeld called “The Surge”, basically using National Guard soldiers for a dirty, hazardous job in another country because we didn’t want to spend the money on regular infantry troops for the same mission.
            Then I blithely agreed to the idea of mobilizing NG troops to do work that the government has decided not to pay full market value for, under military discipline (quit work for that facility down the road who’s paying a competitive wage, and face a court martial and time in Ft. Leavenworth).

            I withdraw my previous suggestion about having the National Guard Bureau search out civilian welders in the Air and Army National Guards and to work for enlisted rank salaries and a much less protective workers’ compensation scheme (lining up at the VA for medical care after shit blows up at the work site).

            If good welding using TIG and other high-skill techniques are worth coercing patriotic men and women into learning how to do them, then ordering them to work for much below the going rate, they’re worth training and hiring civilians to do it at competitive rates.

  12. Konstantinos Spingos says:

    Thank you! Do you have any educated guess about how much a monoclonal for Covid-19 would cost per patient?

  13. Tom Boyer says:

    Thanks for another wonderfully intelligible post. This blog and the MedCram videos both do such a great job of making microbiology understandable for lay people. Learning about biotech here and physiology at MedCram definitely helps make each quarantine day a little more interesting.

  14. Barry says:

    mAbs do solve the scaling and patenting barriers that passive IgG (“convalescent sera”) therapy faces. But as ResDoc points out, the site of action is not plasma-exposed. Would you deliver your mAbs as aerosol to the lung surface as has been done for insulin? Will you treat the whole body as a single pharmacokinetic compartment, delivering mAbs i.v. and hoping blindly that they’ll get where they need to get?

  15. only_an_electrical_engineer says:

    This blog is fantastic but I only understand a slim fraction of it.
    Speaking as someone who has suffered long term (permanent?) neurological side effects from a monoclonal antibody treatment (Humira), I’m eagerly following but extremely nervous about a vaccine for Covid_19, and especially if the solution is a mAb.
    I know I’m not the only one.

    There are clearly some learned folk here so I’d be very keen to hear your thoughts.
    If you already have a messed up immune system from a wonder drug misdemeanour, where does that place you for further treatments that fiddle with your immune response?

    1. Derek Lowe says:

      The eventual vaccine and the mAb will be two different things – a mAb could be both a therapy for sick patients and a “temporary vaccine” that lasts for a few weeks or perhaps even months. But the “real” vaccine will not be an antibody.

      Very sorry to hear about the neurological side effects. From what I understand, those are more related to the mAb’s target (TNF-alpha) rather than it being a monoclonal antibody per se. A mAb for the coronavirus would not affect the TNF-alpha pathways (or really, anything else if it’s a good antibody). So there’s that. . .

  16. ED says:

    Re. Glycosylation: there is a protein-engineering workaround that allows aglycosylated antibodies to work. These can be produced in E. coli.
    See, for example:
    “Bypassing glycosylation: engineering aglycosylated full-length IgG antibodies for human therapy”
    https://www.sciencedirect.com/science/article/pii/S0958166911000413?casa_token=4-ZtO0c9CbUAAAAA:dDv5IcqnYy4JkO8dzBDdKEjVS6WxRF4cTnoJgq6rtJI6Q5B8LPoxSgzQaEMR4qgV0g6rQ2w87Jw

  17. Ed says:

    Leronlimab is the answer and will be in supply by July IMO. Here is description of disease and treatment.
    https://www.researchsquare.com/article/rs-26517/v1

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