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Lots of Coronavirus Antibody News

There’s a lot of interesting antibody news to catch up on, from the early science to clinical trials. A previous post on this subject is here, with links to earlier background explanations, if you would like to catch up on the area. Here, for example, is a report from a large multi-center team in China characterizing two monoclonal antibodies against the coronavirus, both of which were derived from the B cells of recovered patients. The more potent of the two (CB6) was shown to bind to the RBD (receptor-binding domain) of the spike protein, in keeping with many other antibodies that have been described so far. That is, of course, the region of the Spike that recognizes the human ACE2 protein, which is the first step to viral entry and infection.

That CB6 antibody was evaluated in a rhesus monkey model of coronavirus infection – administration of the mAb at day 1 and 3 post-infection demonstrated a 1000x lowering of virus titer in the dosed animals compared to controls, which is good to see. A single dose pre-exposure was even more effective (see the preprint’s Figure 3a for more). On the other hand, the animals were still infected – this wasn’t sterilizing immunity that was conferred – and the dose of antibody was 50 mg/kg. That’s pretty high by therapeutic mAb standards – see, for example,  Table 3 in this review of monoclonal antibody pharmacokinetics, where you’ll see that more typical doses are around 10 mg/kg. But near the end of that table, you’ll see Raxibacumab, which is a therapy against the anthrax toxin and dosed at 40 mg/kg. Then again, there’s also pavilizumab, a mAb used against RSV infection in infants and dosed at 15 mg/kg, so we’re going to have to watch the development of these to see what the dosages (and thus the manufacturing load) will be like. (See below for more on CB6).

And here’s another large effort from a group of Chinese institutions, characterizing 206 antibodies from eight recovered patients. These also show a very strong trend towards binding to the RBD and competing with ACE2 binding, and in fact that competition correlated with the activity of the antibodies in an in vitro assay. The competition assay was better at predicting activity as compared to sheer affinity. Note, though, as in that previous post details, that there are some fine details – not all the RBD-binding antibodies prevent the virus from binding to the human ACE2 protein, although they may well prevent the next step after that binding.  This group obtained a crystal structure for the binding of one of their antibodies (P2B-2F6) and a Spike protein construct, and it does indeed keep ACE2 binding from taking place.

The eight patients studied all raised a different mixture of antibodies, as you would expect – there’s not much more of an individual characteristic that you can find than that. Some of the antibodies had apparently only shown up once during the response, while others had undergone a lot of clonal expansion – and among these, some of them had remained very close to their original form, while others had diverged into a set of related species. This means – and this is no surprise – that giving people “convalescent plasma” treatment from recovered coronavirus patients will necessarily be a variable sort of treatment, since every batch from every different donor will be a mixture of antibodies all its own.

And we’re starting to get more data about that mode of therapy as well. Here’s a study in 103 patients from another large multicenter effort in China. Unfortunately, that’s only about half the patients that they were trying to enroll – the pandemic diminished during the work – and the final study ended up statistically underpowered. There were trends toward improvement in the treated patients, which were more noticeable in the severely ill ones versus the even-worse-off critically ill ones. The other bit of encouraging news was that only two adverse events were reported, with no strong signs of antibody-dependent enhancement. But this is still the most well-controlled trial that we have; everything else is even fuzzier. Things are pointing in the right direction, but we need to know more.

We’ll be getting data from the more-easily-characterized monoclonal antibody trials, though, which have now begun. Eli Lilly and their partner Abcellera announced last week that they had started dosing human patients. Junshi Biosciences  have also announced that they’ve begun human trials of  their JS016, which from that press release appears to be the same CB6 antibody in that Nature paper described in the first paragraph above. They’re also working with Lilly outside of China. Regeneron’s first coronavirus mAb is just about to go into human patients (update: corrected this because they haven’t started yet). (Update 2, June 11: they have now!)  Meanwhile, Vir Biotechnology (working with GSK) published on their own mAb work a while ago (in coronavirus time!) and are expected to begin human trials very shortly as well.

So there’s going to be quite a pileup in trial results soon. But the worry is that there will also be a pileup in the manufacturing capacity. Here’s an article at BioCentury about comments made by the heads of both Vir and Regeneron about that issue, and they’re warning that there may not be enough capacity anywhere to deliver the amounts of these agents that people expect. mAb manufacturing is nontrivial by any of the industrial routes, and by now all the people who can do it have been signed up by one player or another. Just as with vaccine production and rollout, we’re looking at some hard decisions later this year that are going to have to be taken relatively quickly (and on relatively thin data).

Which candidates will look the most successful? Keep in mind that success has several parts – efficacy against the virus, first of all, but also number of doses needed and the total amount of the actual agent that is being dosed. That, as mentioned above, is directly tied to manufacturing capacity. We could end up having to go with a slightly less efficacious treatment that can treat many more patients (and potential patients) versus a better one that has to be given at (say) five times the dose and would thus exceed the human race’s current capacity to produce it. Or versus a better-looking one (remember, these will be on limited data sets!) whose mode of production is just intrinsically more difficult. There will also be considerations about storage and shipment, stability of the production method, and many more: it’s going to be a hard call with a lot of variables involved.

Get ready for it later this summer and this fall, because this could get messy. There are surely going to be a lot of twists and turns, sudden reversals and surprises, and we should brace ourselves for the white water ahead. I think we’re going to come out of it with some real therapies – I really am optimistic about that – but there’s almost no way that it’s going to be a smooth process. . .

57 comments on “Lots of Coronavirus Antibody News”

  1. Mary Scott says:

    Would a patient with administered mAb as therapy gain any immunity? And, for how long would the mAbs be effective?

    1. Zambo says:

      I believe they suspect that it may offer short term immunity (a few months), which would mean it could potentially be given to high-risk populations to bridge the time to a vaccine.

    2. Hanido says:

      Up to a month

    3. Giannis says:

      Antibodies with mutation that increase binding to FcRN should have half lives of 50 to 100 days.

      1. 10 Fingers says:

        Seems like we wouldn’t want to do that – wouldn’t it potentially provide another vector for entry into the cell if the antibody went through normal recycling?

  2. Grumpy Old Professor says:

    While it may be a little tangential, there’s a potentially interesting article on antibody development as a consequence of vaccination, from Sorensen, Susrud and Dalgleish (Norway and the UK: https://www.cambridge.org/core/services/aop-cambridge-core/content/view/DBBC0FA6E3763B0067CAAD8F3363E527/S2633289220000083a.pdf).

    In it, they describe the presence of multiple epitopes on the spike that may generate antibodies cross-reactive with human cells. They also present the notion that some virus-binding antibodies may enhance infection via Fc uptake into phagocytes, as well as other discussion points.

    It will therefore indeed be interesting to see how all of this effort for Ab-therapeutics shakes out, just as DL says.

    GOP

  3. Grumpy Old Professor says:

    While it may be a little tangential, there’s a potentially interesting paper (still in peer-reviewed preprint) from Sorensen, Susrud and Dalgleish (Norway and the UK: https://preview.tinyurl.com/yas4qe59) on the development of antibodies as a consequence of vaccination.

    In it, they describe how there are multiple epitopes on the SARS-CoV-2 spike protein that may generate antibodies which cross-react with human proteins. They also mention that antibody-binding to virus may in fact increase infectivity by Fc interaction on phagocytic cells.

    While it seems unlikely that therapeutic antibodies such as those being developed wouldn’t have FcR binding engineered out, it will nonetheless be interesting to see how this new Ab-therapeutic route works for patients, as DL says.

    GOP

  4. Dr. Wood says:

    To your point about production limits, I don’t think anyone can do with a pharmaceuticals plant what China did with hospitals. You probably can’t build new production capacity in less than a year or two, much less 6 months. Just getting the tanks built (to heck with engineered and installed) will probably take 4-8 months unless you can muscle your way in to get first in line at the factories that make those. And so-on and so-forth, all the way down the line: chemical raw materials, chromatography media, centrifuges, sterile filters, WFI stills, bulk autoclaves, etc. The scale of the infrastructure challenge is stunning. This is a place where Governments could start getting ready, but that would take vision, planning, and a great deal of will, and I am not seeing any of that.

    1. Mammalian scale-up person says:

      Actual lead times for large scale equipment are more like 12-18 months from receipt of signed drawing confirming the designs to mechanical completion (it’s installed and we put water in, but not fully tested and qualified). Add another 9 months – 1 year for qualification. You can shorten this *A BIT* by designing equipment as “family groupings” where all process hold tanks have similar geometry and therefore similar cleaning / sterilization / mixing patterns, and then one validation may be applied to several individual pieces of equipment, but you’re still talking shortening it to 6-9 months. Buy all standard everything, not a hair of innovation or novelty – for some reason, this is always the hardest thing to get people to do, they always want to try something fancy, but fancy == time spent on ramp-up and extra validation work.

      This assumes you have a design ready to go; most manufacturers do, though – they’ll have an existing facility that operates at least half-decent, and they’ll tell the A/E firm to just make another, and hand over the original drawings. Still, getting to the point of confirming all the drawings and designs that already exist, and getting them signed off, tends to take a solid 6-12 months. And again – there’s always someone who wants to tweak the design somehow, change something they don’t like about the existing facility, and rarely does anyone in senior management bark at them to hold their thoughts for the next project, we’re signing off on this due to time constraints. Instead, they do the dance of “let’s have meetings with all the stakeholders so everyone can put their $0.02” and you get too many cooks in the kitchen.

      And then you have to hire staff, and train them. Easy enough to hire staff quickly in some locations…others, not so much. So, you’re confined to biotech hotspots for locations if you want to hire quickly, which also happen to be the most expensive real estate and salaries. Your other option is automating a lot more, but then validation takes twice as long, and additional CAPEX spending is an issue, and you still have to hire the automation people.

      Utilities and permitting can definitely hold up the process further – I’ve seen one project that has been basically On Hold for 10+ years due to wastewater permitting issues. Yes, government can help…but seems unlikely to at this point.

      I hope it doesn’t come down to “what are we not going to make?” But a lot of the newer plants are small scale single use. Even if we had high titer cell lines, the downstream purification operations will be overwhelming.

      1. Churlish says:

        Thanks so much for your insights on this post and others on this blog, Mammalian scale-up person.

        I had a general understanding that you can’t just push a putton and scale up production of a mAb, but it’s so valuable to learn exactly how much is involved and how much time and effort it takes.

      2. Anon says:

        Appreciate your viewpoint, but if there ever was a time to challenge the traditional doctrinaire approach to scale up, tech transfer, IQ/OP/PQ the time is now. Yes I am fully aware of ISPE, PDA etc requirements and how sound their basis is. Nevertheless, we will need to trim down our red tape to the minimum in this time of “war” without compromising safety and efficacy. It can be done.

      3. wubbles says:

        In 1940 the total US production capacity of Plutonium was 0. It hadn’t even been discovered yet. In 1943 the US army broke ground on the B-reactor which had by 1945 produced enough for two bombs. In 1940 US B-36 production capacity wasn’t one plane an hour. By 1945 it was.

        1. NotADoc says:

          It was a different country then. There’s a reason they’re called the Greatest Generation, the Boomers are called the Me generation, and the Boomer’s spawn are called … names I can’t use here 😉
          Such is the arc of civilization, it’s hook shaped and it bends towards garbage.

        2. Carl says:

          You have to understand WW2 had a truly obscenity inducing amount of money thrown at it. At the height of the war the US was spending just under 40% of it’s GDP per year on the war, (around 7.5 trillion USD in today’s terms, almost 4 times what the US government has spent on COVID-19 measures so far), whilst any single project only used a smaller percentage of that where still talking enormous sums of money, (note the cost of the manhattan project in today’s money isn’t entirely indicative, the cost of some things has not increased at the rate of inflation and these would likely inflate the costs), which world governments may be loathe to shell out on top of allready exist costs allready incurred coping with the virus.

        3. topquark says:

          …fast neutrons do not an antibody make…

          The Manhattan Project is not relevant to this problem.

          1. Carl says:

            Topquark, he could as easily have brought up the mass production of penicillin during ww2 which used much of the same principles as all the other war effort projects when it came to doing a lot quickly, (which mostly came down to throwing lots and lots of money at the issue).

            So actually yes the Manhattan project does have some bearing here at least insofar as it’s an example of the ability of sufficient pressure and money to yield extreme positive results in an extremly low end time frame.

            But again as i allready pointed out further up, the amount of funding required to pull that off in today’s terms would be so astronomically high that i don’t think any government is going to do it.

          2. Ian Malone says:

            Indeed. The Manhattan project by July 1945 had enough plutonium to produce two bombs, the Trinity Gadget and Fat Man. Little Boy was a uranium device, which they were fairly sure would work and so didn’t test, partly due to lack of material.

            Imagine that in two years we might have enough antibodies to treat two people.

          3. loupgarous says:

            Biological warfare and antibiotics in WW2, however, were two heads of the same calf (grazing at Vigo County, Indiana).

            By 1944, the Vigo Ordnance Plant had orders to make 500,000 anthrax or botulinum bombs. DIfficulties in containing the bioweapons pushed production of anything but simulant weapons (b. globigii) off into 1945, and no actual biological weapons were made at Vigo. Pfizer leased the site in 1948 to make veterinary antibiotics (streptomycin).

            The fermenters readied for the US Army’s BW program were used by Pfizer to make penicillin… so roughly the same time range obtained as did from Glenn Seaborg’s experiments to make plutonium to full production of plutonium at Hanford..

        4. Mammalian scale-up person says:

          Yeah, so here’s the problem – which I agree can be solved! but…not quickly.

          In order to make equipment to make antibodies OR refined plutonium, you need steel, and you need foundries, and you need a lot of cheap energy. In the 1940s, there were LOADS of US-based foundries. You needed steel – just mosey on down to Bethlehem or Pittsburgh PA, they’ll hook you up with all the steel you can eat, cheap. Raw materials manufacturing was widely distributed and there were several sources for raw materials, not the “globally distributed but only a couple of actual sources” situation we have today. When we need steel in mass quantities now, we have to ask China and a couple of other countries very nicely how long it might take for them to get around to making it for us. Except…the pandemic is global, so the answer is “not for a while, really”. Everywhere. There is no distributed network of foundries to make equipment or weird vitamin mix manufacturers to make cell growth media or resin manufacturers to make purification resin – there’s less of these than I can count on my fingers in the whole world, and they’re also in regions that got slammed by the virus.

          It’s not actually that different a problem from drug shortages of antibiotics and generic small molecules – there’s only a few sources in the world at the moment, and creating a distributed network that is more robust is not a trivial undertaking – with no financial incentive to do so for private industry. It’s a lot easier to scrap a facility and sell everything on Godovebid than it is to build a new one, and the financial incentives are for short term savings, not long term overall economic stability – that’s what the government is supposed to do with economic policies, which we did for quite some time in Puerto Rico (see: Amgen, AZ, BMS, Merck, Lilly etc).

          Now, here’s another economic conundrum, which I think partially answers the “why nobody is going to invest that kind of money” question: European and Asian countries have mostly gotten this disease down to a slow burn. A lucky few have nothing but cinders left (congrats, New Zealand). The US, Brazil, and Russia, however, are still churning out infections – we don’t even know how many really, and we know Central and South America don’t have the infrastructure to achieve the kind of containment that the European and Asian countries achieved, though the Central American gangs are doing what they can. We think, probably, it’s somewhere between 1-10% of the population in the US already infected, depending on where you live, at ~4 months in. Many states have decided to re-open despite their not-great numbers. By the time a vaccine is ready for the market, even if that is on an extremely accelerated timeline of only a few years, the only markets left for it may be Europe and Asia. Everyone else will have already become infected. Unless it becomes a seasonal thing like influenza, there may very well be no point in scaling up to that level. In your Manhattan Project example – what if in 1945, everyone held hands and sang Woody Guthrie songs and Pete Seeger never had to write “Where have all the flowers gone” and Lockheed-Martin made little passenger planes for ever and ever? Who can stand those kinds of sunk costs, other than the government? Not private industry, for sure.

          1. Thomas says:

            What about using foodstuff equipment manufacturers? They are still around locally and have their stainless steel tanks, autoclavs and whatnots of the big items.
            That probably leaves a whole lot of ‘other’ stuff though. But thinking outside the range usual suppliers could get us there.

          2. Mammalian scale-up person says:

            Thomas – we already do, to some extent they already have considerable crossover (GEA, Alfa Laval, several others). There is a difference in the steel quality allowed (316L electropolished to <20Ra vs 304) per ASTM specifications, but they are the same manufacturers by and large.

            We don't use as much process analytics as food/bev, we don't do the pigging method of CIP as a rule, and one of the BIG issues we run into with people who come to pharma from food/bev is the free draining & steam-in-place requirements of the BPE addendum to the ASTM piping standard. You want to see a project go straight to heck right quick, put a food/bev piping designer in a pharma plant…you'll have to rip out everything he does and start over. Ask me how I know…

          3. P Burgos says:

            Wouldn’t China want the monoclonal antibodies as soon as possible if for no other reason than to help the global economy, and hence their economy? Having the monoclonal antibodies would also be a diplomatic coup for China, allowing them to either drive hard bargains with other countries in need of them or perhaps the party would decide to be fair about things in order to build up global goodwill towards their regime.

            It sure seems like it would be a lot cheaper than the Belt and Road Initiative, and the good press it would generate among Chinese people could be invaluable to the regime.

          4. Mammalian scale-up person says:

            P Burgos – Sure! So does Europe. But, making mAbs for just Western Europe and APAC is much MUCH less of a manufacturing proposition than making mAbs for the whole world – now you’re talking about perhaps two large facilities’ worth of production, as opposed to a half-dozen entire facilities with 6 bioreactors each, all running at once. If we’re talking about a much smaller patient population limited to one region, there’s already *some* existing capacity for that. Telling WuXi they need to make enough mAb to treat half of China, and they’ll need to build a couple of new facilities – that’s a much easier proposition than “make enough mAb for the entire world”. It will still take two years to build the new capacity, but it’s a lot easier to shuffle around a network to put out, say, 10 batches here and 20 batches there for a while than it is to suddenly make 500 batches per year.

          5. Single Use Bag says:

            But in all fairness, I do wonder if this is also an opportunity to advance the manufacturing technology. If continuous processing actually works, now’s the time to deploy it in a broader setting. Not being an expert and not knowing what batch sizes would be needed, I still wonder if Single Use can help at least alleviate the bottle neck due to shorter set up times.

            Lastly, haven’t many of the Korean CMO geared up for the Biosims launch in Asia? There it will indeed become a question of priorities/financials…

          6. Mammalian scale-up person says:

            SUB – definitely agree on continuous and single use! It does indeed work, and a lot of the barriers to making it work on the cell culture side (perfusion was difficult to keep sterile for a long time, due to lots of stainless steel connections that loosen up and bend a LOT more than most engineers anticipate with heating and cooling cycles) have been resolved.

            Samsung Biologics has indeed expanded significantly, but most of their stuff has been pretty small scale and their batch success rate is not great – you can tell by the mismatch between the cell culture capacity and the downstream purification capacity, they’re losing batches.

          7. Anon says:

            Adding to my comment about cutting down on red tape…The point is, both for large-scale mAb and vaccine roll-out, we’re going to have to pare down a lot of the operational cGMP rules to the bare minimum needed, parsing between the “must have” versus the “nice to have”. If the global population is in an Alamo-like situation, a lot of the niceties that go on in pharma production will have to be reassessed. More importantly, there should be high leadership and CMC-reviewer-level involvement from FDA in real-time, during planning and execution for these development activities. The traditional model where you write protocols, execute them, submit them in an application and then wait for FDA feedback in CRL cycles will be ridiculous under current circumstances. I write this based on my tech. transfer, scale-up and commercialization experience as well. The multi-million dollar/human lives question is whether the Agency has the genetic ability to start behaving in such a proactive fashion? Ideally, there should be an FDA person in-plant (yes, I know no one would welcome that!) during every step so the approval accompanies the end of scale-up. On the other topic you bring up, the offshoring of manufacturing capabilities to now-hostile shores, all I can say is that “globalization” at its heart, was basically an exercise in labor cost arbitrage. All it did was enrich the capital-holders, who pocketed the surplus at the expense of the citizens of the off-shoring country. But that’s a different discussion. Right now, we’re going to have to creatively cut corners, ignore expected ways of working, etc. etc. and deliver life-saving S & E product.

          8. David says:

            Wow well said!

          9. Mammalian scale-up person says:

            Anon – I don’t disagree with you, and in fact having a person in plant and QA on the floor has been in my experience a big help. A METRIC FRIGGIN TON of deviation-resolution and QA stuff I have seen comes from comment written at 2am by a tech who had been working 14 hours, didn’t describe the situation absolutely 100% perfectly, QA reviewer hadn’t seen a manufacturing floor in over a decade and had no idea what they meant by “welder” or “probe port” and immediately jumped to a conclusion, then various other management (also decades away from the manufacturing floor) getting involved, all of them refusing to gown up and just GO LOOK AT IT, PLEASE, FOR THE LOVE OF GOD JUST LOOK. Then when we finally bring one out to the conference room to see for themselves (because bringing stuff out is at best a big effort to decontaminate, sometimes impossible), it’s all, “oh. Oh. That’s it? Really? Huh. Never saw one before. Oh. Oh. I see. Um. OK. We’ll just…uhh…make a note in Trackwise…I guess…” All that nonsense is avoided with a person-in-plant who understands the facility and has a much more intuitive grasp of what’s going on. I love it, I absolutely agree with you. *BUT*- I don’t think FDA has the staff for this. They don’t have adequate staffing to get done what needs to be done now. And hiring enough staff would not be a trivial undertaking by itself. I agree with you that they should, but there is zero political will for it to happen.

            There are other tricks: I used to have SAT consist of a drawing walk-down, wiring and weld checks as soon as the equipment is uncrated in the receiving dock, then bring it to the floor, hook up the WFI drop, and have a completely automated I/OQ that was also SAT. I had a nice program that beeped its way through alarm testing, sensor testing, pump calibrations, valve checks etc. all by itself, then I could pull trend reports after 2 days. Then I spent a day doing user training on it, and that included the security access checks and creating the user accounts. Since it was run by mostly automation, all the documentation was created along the way in the historian and things could be scheduled so the user training happened daily on something, somewhere. You can also run CIP cycle development based on inline TOC limits for each phase, and over-slope your piping to hit your SIP F0 quicker – one of my bosses used to do 7degree sloping on his piping, and he never had an SIP failure in 30 years. But, I was able to do that because I was constantly building stuff for years on end – so many validations are treated as a one-off, because how often do most companies have a major expansion? Why should protocols for validation of the same dang stuff EVER be written as one-offs? 95% of the stuff we write protocols for is all the same thing – there’s not that many different ways to validate load cells, other than putting calibrated weights on the damned things. There’s not that many different ways to verify flow rates across a PCV, there’s no reason all this can’t be a standard method, so why do we write the protocols and reports as if this is all some completely novel technology? It’s silly, we can definitely do this faster and easier.

            That said, I’ve seen companies who act like the compendial methods for qualifications are some crazy, novel, debatable requirement they can somehow weasel out of or never heard of in their lives. This tends to be highly correlated with companies that manage by committee meeting…

        5. Alan Goldhammer says:

          @wubbles – you need to get your facts straight. The B-36 was not used during WW-II. It’s first flight was not until after the war ended. My dad worked at Convair as a project manager during the war on both the PBY Catalina and the B-24 Liberator. We went down to Lindbergh Field in San Diego to see the final plane off the assembly line take flight. I think this was in 1954 when I was seven.

        6. J Goodman says:

          Look how much trouble we’ve had scaling up N95 mask production, which I’m guessing is orders of magnitudes easier than mab production.

  5. Thoryke says:

    I imagine that any tx that prevents viral binding at the cost of snarling the existing biologic processes that rely on ACE2 binding would also be a no-go. And I’d hope we’d detect that long before human trials; nobody wants a repeat of the TeGenero trials!

  6. Barry says:

    The first Chinese paper characterizes Abs recovered from convalescent serum. That’s gonna be IgG, rather than the IgA needed on the the respiratory mucosa. That after all is where the Covid19 infection happens. Although “Class Switching” can couple production of IgA to IgG putting different conservedFragments onto the same variableFragment, the response to a vaccine is going to depend critically on the route of inoculation and the adjuvant(s) used.
    As I’ve observed before, inoculating with BCG is quite effective at eliciting IgG and at protecting against miliary tuberculosis. Where it fails is in protecting against the air-borne infection to the respiratory tract.

    1. RA says:

      Really interesting point! Would we expect it possible to increase IgA in the nasopharyngeal mucosa through intranasal inoculation? And why isn’t there more attention to this point, given existing candidate approaches are not sterilizing this area and shedding here is driving the spread?

      1. johnnyboy says:

        This is something I don’t understand about all the vaccine work – I have not heard of any effort to target IgA production rather than IgG (ie. with intra-nasal or inhaled inoculation, rather than subQ/intramuscular, or IV for RNA vaccines). While having a good IgG titer will likely protect against the more severe systemic phase of the disease, it is unlikely to prevent at least some replication cycles in the respiratory mucosa. Unless a standard systemic vaccination (subQ or IM) can lead to sufficient IgA production ?

    2. Barry says:

      I’m no immunologist! But it looks like IgA delivered i.v. would get ‘ported by respiratory epithelia to the site of action on the apical side. I.e. clever choice of the Fc for mAbs could get mucosal immunity.
      As to vaccines, choice of the route of inoculation, and choice of adjuvant(s) is critical in eliciting IgA response.

      https://www.sciencedirect.com/topics/neuroscience/secretory-immunoglobulin#:~:text=The%20secretory%20component%20is%20produced,released%20into%20the%20mucosal%20environment.

  7. David Young MD says:

    Good question. They probably would get less immunity, since giving the monoclonal antibody intravenously is lessening the viral load right away. One might suspect that there would be less virus to invoke your own antibodies and memory T-cells, memory B cells. But since there is still some virus there, you might well make some antibodies.

    As an oncologist, I have a lot of experience with giving monoclonal antibodies for certain types of cancer. For lymphoma, we give Rituximab (Rituxan). This is given at a dose of 375 mg per meter squared and the highest dose would be 800 mg in a large person. Typical doses are 600 mg to 700 mg. Because of the high antigen load, the very first infusion is given slowly, sometimes over 6 hours or so. A person would experience chills, rigors, fever, flushing, tachycardia and difficulty breathing if given rapidly. The second dose is much better tolerated. Rituxan stays in the blood for 6 months

    Denosumab is a rank ligand antibody, given as a subq injection with no side effects. It stays in the blood for almost six months.

    Remecade, for rheumatoid arthritis is given as an infusion and seems to last for about 6 to 8 weeks.

    Vectubix is given every two weeks for certain colon cancers.

    Obinutumumab, for chronic lymphoid leukemia is given months, after a loading dose schedule. The very first dose is 1/10th the dose of latter infusions and still, without fail, causes severe chills and rigors (and probably should be 1/30th the typical dose, except that the FDA will not let us do that.)

    Tysabri is a monoclonal antibody for Multiple sclerosis and is a fixed dose of 300 mg monthly, normally limited to 6 doses.

    Monoclonal antibodies tend to be very well tolerated, except for the very first infusion

    Most of these doses come to about 500 to 750 mg with the Tysabri being somewhat lower. Giving 50 mg per kg would come to 3,500 to 4,000 mg for an average person… quite a dose. And if there are infusion-related reactions, the first infusion might take 8 hours or so. If the patient is hospitalized, then… no matter, they can infuse the drug over 14 hours if necessary.

  8. bacillus says:

    With respect to the polyclonal nature of human convalescent serum, I would expect that for therapeutic use, they will be combining blood from multiple individuals per batch which should overcome any issues of inadequate epitope coverage that might otherwise arise.

  9. Dr. Manhattan says:

    A general question: Does anyone know of any efforts with camelid single domain nanobodies as potential CoVid19 therapeutics? There are now bacterial and yeast based systems to both select and express these single heavy chain molecules, and they might be an alternative to the more traditional production challenges of monoclonal antibodies discussed above.

    1. Mammalian scale-up person says:

      Ah, the camelbodies (as we called them at Wyeth in Ye Olden Dayes)! Which were quickly followed by the “nanobodies” from dogfish sharks.

      Just small companies I believe. Ablynx got bought by Sanofi and just had approval for anti-VWF, but it took them quite some time to get a hit. There would still be concerns about immunogenicity (both positive and negative in the case of Covid) and frankly it doesn’t matter whether you’re fermenting or culturing at that scale, you still need a bunch of big steel tanks, piping and purification systems aren’t very different at all – in fact there would be a significant disadvantage in the process validation timeline because the camelbodies are not as well-trodden a path as mAbs. The sparger designs are different, but everything else is very similar. At the point of “make doses for 10% of the world’s population” whether your bioreactor aspect is 1.5 or 3 doesn’t make a lot of difference.

  10. jbosch says:

    From previous convalescent plasma studies, it is thought that anywhere between 2-3 months would be your protection level. But in case you get infected during that time, you may be able to generate your own antibodies as well. But for a prophylaxis there is not enough convalescent plasama available. If the mAb’s work, that would be a very good solution. However, they still have to be injected, kept cold etc. So could be problematic for countries in South America or Africa.

  11. Giannis says:

    There are some developemnts with utilizing pIgR to make engineered IgG cross the epithilial barrier. Hopefully this will be investigated since it might reduce the required IgG concentration by orders magnitude.

  12. dearieme says:

    Someone somewhere is sometime going to wonder if he should do what he can to keep the pandemic going so that he can profit from a vaccine. What strategy would he adopt?

    How about funding some huge riots/protests?

    (You may suspect that I am parodying conspiracy theorists. Maybe.)

    1. Let 'em eat ivermectin says:

      Free business advice to evil Big Pharma: Don’t pay for what you can get for free. People love to protest. It’s like paying people to get drunk on the weekends.

    2. Lappan says:

      Seems simpler just to turn up the power on the 5G towers.

    3. loupgarous says:

      Far be it from me to feed conspiracy theories, but… the Perseus-Soros BioPharmaceutical Fund LP’s Web site isn’t shadowy at all. They’re the Soros family’s foot in Pharma VC.

      Their mission statement: “Perseus-Soros BioPharmaceutical has been established to make investments in life science companies developing biopharmaceutical products and creating businesses based on advanced life science technologies. Companies targeted for investment will have the potential to achieve profitability in a reasonable time period, to maintain a dominant position in selected therapeutics areas, and to address large markets with unmet needs.”

      The political side of Soros’ work is more shadowy. You don’t need to be even slightly right-of-center to think so.

      In fact, the more to the Left you, the easier it is to see that the progressive movement Soros funds, from soft money for the Left’s Congressional campaigns, even unto big protest movements like Occupy, are the 1%’s way of hedging their bets.

      Alexandria Ocasio Cortez went briefly on record as celebrating the pandemic and the crash in the oil market it caused in the Twitter equivalent of an open mike moment.”

      “You absolutely love to see it,” wrote Ms Ocasio-Cortez. “This along with record low-interest rates means it’s the right time for a worker-led, mass investment in green infrastructure to save our planet. *cough*”

      Her timing, smack in the middle of thousands of COVID deaths in her home district, could have been better. Fortunately, she belongs to the Party of the Unscrewable Pooch, so the mainstream media deleted their reporting of AOC’s gaffe not long after she deleted the gaffe itself.

      But the gaffe wasn’t just the gaucherie>/i> of celebrating the deaths of a million people so your and your friends (the “workers” contributing to union pension funds, foor example)could buy everything on the Market up cheap with a theatrical *cough*. Of course, those pension funds may be wisely guided in their equity buys by the corporate sponsor of American Progressivism, who just happens to be a venture capitalist (among other things).

      A billionaire investor savvy enough to invest in radical futures might want to have millions of people out on the street mingling and incubating SARS_CoV2 just as much as other billionaires who want to do business while their business assets are still worth something.

      Because just one conspiracy theory isn’t plausible on its own.

    4. loupgarous says:

      Now I”ve written the plot out for a Bond movie, a really smart evil genius would let the grinds invent vaccines. A venture capitalist with lots of other people’s money (union pension funds, say) to play with, don’t need no steenkin’ vaccines.

      When the markets bottom out he buys everything up cheap. Eventually the world economy rebounds, and his social justice warriors learn that he doesn’t believe in defunding the police – he may, at some point, be one of Erik Prince’s first post-pandemic customers.

      Even if he had the necessary money to play Bill Gates, It’s probable he won’t. He’s already bought a few countries up at the legislative level.

  13. myst_05 says:

    Do we have a reason to believe that antibodies can be manufactures on a meaningful scale before get a vaccine ready?

  14. TallDave says:

    what are the bottlenecks? what are the alternatives? how much can we do in the time we have?

    given that trillions of dollars and thousands of lives are on the line (seems very likely sufficient qtys of synthetic antibodies could quickly crush the pandemic with very little additional loss of life) these supply chain questions need to be addressed publicly asap

    1. Barry says:

      search the various contributions from “Mammalian scale-up person” this post and related. There’s an education for us all in what’s involved in implementing/deploying biologicals to market

      1. Derek Lowe says:

        True, those are quality comments on a topic that not many people know in much detail.

        1. TallDave says:

          are we asking the right questions, though? do we really need more production capacity?

          remember all that panicked ventilator production investment from just last month that we will probably regret?

          how does current production capacity of the relevant factors compare to the amount needed to treat the entire *currently* hospitalized COVID population (remember, in China this is now supposedly zero)? if infection rates plunge after a cure is available, supply may exceed demand very quickly

          perhaps there should be some public focus on sharing resources across as many candidates as possible

          also after six months mRNA vaccines seem likely to be in mass production, who knows where the infection rates will be by then though

          1. TallDave says:

            CDC seems to think hospitalizations are currently about 20 per 100K so being cautious maybe 80K in all… seems to be trending down but there are a lot of disclaimers attached so 80K seems like a reasonable place to start

            presumably ideally we would want to give antibody cocktails to their recent contacts as well, so maybe a million doses in all for the US to start (but probably rapidly declining from there), with an emphasis on the first 100K for those actually ill?

  15. Ice Man says:

    by the time a vaccine would be approved and produced in mass scale, it might be too late. There are many reports regarding the virus being slowing down 3-6 months after reaching its peak. In Italy there was a study that suggested it’s also not as violent as it initially was in the early stages, so maybe DL can find some more data regarding these new studies in one his next blogs. We’re also learning lately that A-symptomatic patients are low risk, after we’ve learned that surface infection also rarely exist. Could it be that what we are witnessing is the slow diminish of this pandemic?

  16. TallDave says:

    e.g. “volumes of antibodies that will be needed to treat potentially tens of millions of people are formidable,” said Scangos

    sure that’s true but “tens of millions” is more of a long-term problem, at least in the US

    assuming you keep giving the initial doses to only the people actually hospitalized until all of them have had it, guessing you need maybe 200-300K effective doses to get to the point where every hospitalized person in the US has had it and stocks are growing faster than new hospitalizations? (daily new hospitalizations seems to be around 10% of total current hospitalizations)… of course also depends on whether production is (say) 10K per week vs 100K per week… time vs capacity

    and at that point death rate hopefully falls to near zero and people can begin to get their lives back

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