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Clinical Trials

Monoclonal Antibody Data

We have a bit of human clinical data from the Eli Lilly/Abcellera collaboration to make a monoclonal antibody therapy against the coronavirus. A full paper is coming soon, the press release says, but for now it looks like this is all we have to go on.

It’s a mixed assortment of news. On the cheerful side, in mild-to-moderate recently diagnosed patients, a dose of 2800mg of antibody did lower viral loads, and there were no adverse events. The prespecified mark was Day 11, but it appears that pretty much everyone in the trial, including those getting placebo, had very low viral titers by that point. Further analysis showed that the antibody treatment also lowered it at Day 3 (by an unspecified amount) and lowered the number of patients with persistently high virus at later time points (although we don’t know how many people were in that category). The other good news is that another prespecified endpoint (number of patients who went on to hospitalization) seems to have been significantly lower in the treatment group (1.7% of them as opposed to 6% in the placebo/standard of care group). The release notes that most of the hospitalizations were in patients with known risk factors, which suggests that that antibody might be best targeted towards these groups.

But now the less good news. The trial looked at 3 doses: 700mg, 2800mg, and 7000mg, and there was no dose-response: only the middle dose worked. That’s worrisome; I’m having a hard time figuring why the higher dose would not have shown effects (and I’ll bet that Lilly is, too). This was not a tiny trial, but it wasn’t huge either (about 300 in the treatment group and 150 in the control), and there’s a nagging worry that the effect size just wasn’t large enough to see a solid answer in a group this size. I would have to think that Lilly expected better, and that’s why the trial was designed with this number of patients. And when I say “solid answer”, that cuts both ways – if that’s the statistical problem here, then a larger trial might show the 7000mg dose having some benefit, but it might also show that the 2800mg dose didn’t. These are the thoughts that a lack of dose response provokes.

Lilly and Abcellera are still in the clinic, with this antibody and another candidate that binds at a different epitope on the coronavirus Spike protein. They’re testing the combination in a larger group of higher-risk patients, and I very much hope that the data that come out of that trial are more solid than these numbers, which are honestly weaker than I expected. The combination is similar to what Regeneron is in the clinic with now. It’s worth noting that the press release mentions that coronavirus mutations that would lead to resistance against this single antibody were seen in about 6% of the controls and 8% of the treated patients, which is reason enough to think that the combination could be a better idea.

The other issue that these numbers raise is the dosage. For the hypothetical 70kg patient, a 2800mg dose is 40 mg/kg, which is about what had been ballparked for a therapeutic mAb in infectious disease. And of course that was a lower dose in the high-BMI risk group patients, who seemed as if they might have responded better to the therapy. But any way you look at it, that’s a lot of monoclonal antibody to produce and to dose. The companies involved know this, of course, and have been anticipating it, but that makes it all the more important to find out what patient groups will benefit the most from the treatment. This is not going to be something that’s rolled out to hundreds of millions of people.

Matthew Herper has a good story on this release in Stat, and he has a statement from Lilly that they’re considering asking for an Emergency Use Authorization. I think that’s a bad idea. For one, these data (although promising in some ways) are not so promising in others, particularly that lack of dose-response, the fuzziness of the readout on overall efficacy, and in the possibility of resistant mutations with the single-antibody therapy. This one needs to go back into the oven, I’d say. An EUA might well make things worse for the mAb-versus-coronavirus field overall, because it could well disrupt the trials that are already underway. We’ve had a fiasco in the convalescent plasma field already; we don’t need one for the targeted antibodies as well.

75 comments on “Monoclonal Antibody Data”

  1. Matthew says:

    Two questions:
    Can this be used prophylactically?
    What is the effect on the longer term immune system itself with regard to responding to SARS-CoV2 infection?

    1. David E. Young, MD says:

      I recall that one of the Regeneron monoclonal antibodies is being offered in a randomized trial to household contacts. So that question should be answered “in principle” before long

  2. Thomas says:

    If a mAb doesn’t work for a specific epitope, does that mean a vaccine with that epitope will also not work well?
    Or will the vaccine cause the immune response to trigger quicker, and will antibodies for the virus itself be created and not just for the epitopes in the vaccine?
    (Without any infection, the antibodies would be limited to vaccine epitopes – which might be limiting).

    1. Marko says:

      I don’t think you can reliably predict the results of a polyclonal immune response to a vaccine based on the results from a monoclonal trial. With the vaccine’s polyclonal response , you’re going to get a number of antibody specificities and affinities to even relatively small antigens , not to mention a range of antibody isotypes and subtypes , plus cellular adaptive immunity and perhaps a jolt to innate immunity as well.

    2. Marko says:

      This thread by Shane Crotty describes their new paper in Cell that outlines what an effective adaptive immune response looks like. A MAb can’t do it all , but it might give time for the immune response to kick in , particularly if given early. It seems the big problem is that the elderly don’t mount an effective T-cell response , which a good vaccine might be able to overcome :

    3. Valdis Andersons says:

      The paper linked in this article:

      Explains it really well. The differences between naive and non-naive immune responses are quite different. A vaccine is intended to make the immune system non-naive.

  3. TallDave says:

    somewhat disappointing/confusing, wonder if there are delivery problems

    otoh this seems promising and they say this result was pooled across doses

    “These biomarker data correlated with LY-CoV555’s positive impact on the prespecified endpoint of COVID-19-related hospitalization or ER visit. This endpoint occurred in 1.7 percent (5/302) of LY-CoV555 patients, pooled across dose groups, as compared to 6 percent (9/150) of placebo patients, which corresponds to a 72 percent risk reduction in this limited population.”

    overall impression is: more data please!

    at least a dozen more candidates also seem to be in the pipeline

    also have to hope we are also getting more calcifediol/Vit D studies as they have seen similar correlations

    1. Marko says:

      “…also have to hope we are also getting more calcifediol/Vit D studies as they have seen similar correlations ”

      Indeed. And using about 1000x less drug / less cost / less chance of adverse reactions. But also about 1000x less exciting / less blogworthy / less profitable , i.e. , the IMPORTANT stuff.

    2. David E. Young, MD says:

      Well, there are roughly 50 vitamin D studies worldwide right now.

      1. Marko says:

        According to a report by Dr. John Campbell , Dr. Fauci is taking a daily dose of 6000 IU. Fauci must think the data is compelling enough already regarding the benefit/risk calculus for himself , so why not make a recommendation to the general public , even if it required adding caveats ?

        First couple min. of video , here :

        1. Patrick says:

          So just to be clear, our source for Fauci taking vitamin D is a UK based youtuber? Is there any particular reason to believe this claim, like another source?

          1. Marko says:

            “So just to be clear, our source for Fauci taking vitamin D is a UK based youtuber? ”

            So , just to be clear , our source for Dr. Fauci taking Vit D is Dr. Fauci. Straight from the horse’s mouth. On video , here (~32 min in ) :


            The update today was the dosage , which appears to have been obtained in an email exchange initiated by a viewer of the above video. It looks legit to me , but make up your own mind . If you want to follow Fauci’s lead , though , you’ll supplement with Vit. D at some dosage.

            I suspect his dosage regimen will be confirmed by him over the next several days , as he’s sure to be questioned about the reported email exchange. If so , then you can adjust your dosage to match , if desired.

        2. Riah says:

          Well this RCT from Spain published 29 Aug had pretty spectacular results for the vitamin D group. Nil deaths v 8% (Ok non significant because of small numbers) but need for ICU drops by 96%:

          Lots of other recent research (including from Yale) shows T-cells are critical (not so much antibodies) for successful response v COVID . And of course T-cell activation is totally vitamin D dependent.That is long established from 2010: ” In order for T cells to become active members of the body’s immune system, they must transition from so-called “naive” T cells into either killer cells or helper cells (which are charged with “remembering” specific invaders). And, if ample vitamin D is not around, the T cells do not make that crucial transition, a group of researchers led by Carsten Geisler, head of the Department of International Health, Immunology and Microbiology at the University of Copenhagen, found. They draw this conclusion based on their experiments with isolated naïve human T cells”
          Further comprehensive review on COVID and vitamin D:
 Section 5 of the review is of most relevance .

          1. TallDave says:

            yeah the 25-fold reduction in ICU was eerily reminiscent of the 20-fold reductions in mortality associated with higher D levels in the PHI study

            really seems very promising

  4. J Sanders says:

    The “problem” is that only 6% of the patients in the placebo group required hospitalization. With such a low event rate in the control group a large n value will be needed for these types of studies.

    1. Rob says:

      Yes. I think the standard deviation for the difference in a sample like this is about 2%, so about 4% for significance. They need a bigger sample or sicker patients.

      1. Chris Phillips says:

        I can’t see any claim of statistical significance in the press release. Wouldn’t they have mentioned it, if the results were statistically significant? Or are we assumed to be so dumbed down now that this wouldn’t be in a press release?

        1. J Sanders says:

          Not sure this is the proper test….. or if it is appropriate to combine treatment arms… but a Fishers test comparing hospitalizations between placebo (9/150) and the combined treatment arms (5/302) comes back as a p value around 0.02

          1. Rob says:

            Yes. With a difference in proportions of greater than 4%, you should get a p-value of less than .05.

  5. Some idiot says:

    Wow… 2 – 7 g per dose… I thought it was a typo until I read the press release…! I’m only a small molecule process guy, but that sounds like a lot… Having said that, if one shot is the entire treatment, then that helps a lot… but still…!

    1. David E. Young, MD says:

      Seems like a lot. My practice uses a lot of Rituximab in treating lymphomas and such and the typical dose is 650 mg weekly for 4 weeks, repeat every 6 months. This dose is based weight and height. For Rheumatoid Arthritis, Rituximab is given as a standard dose for all, 1 gram twice (a week apart) although some specialists give much less. Gazyva starts out with 100 mg, then 900 mg the next day and then 1,000 mg every 2 weeks and then every 4 weeks. So, anything at 2,000 mg sounds like a lot and 7,000 mg a whole lot.

      1. johnnyboy says:

        It is very much ‘a lot’. There is no theoretical limit to the amount of protein you can administer as a drug, but in general when you get to the gram range it starts giving people pause. IV administration issues, possibilities of reactions, anti-drug antibodies… who knows, we’re a bit in uncharted territory here. My company has experimental oncology drugs that need to be administered in the 1-3 g/dose range to have a PD effect, and that level is certainly raising a few eyebrows with the safety people. Not to mention the manufacturing issues, for something that could theoretically be given to hundred of thousands of patients in a short period.

        1. Mammalian scale-up person says:

          I’ve had rabies prophylaxis, which was about 2 g, and due to the infusion reaction you mention, they administered it IM. Since the maximum concentration of IgG before it turns into a thick syrup too difficult to inject is about 150 g/L, this was still a fairly large volume for an IM injection. My god, if I ever have to have an injection like that again, they better be sure that I am dying. If I had to have three or four of those damned things? Formulate it with lidocaine and give me Versed, please.

  6. Anon says:

    As a protein biochemist in early/fundamental research, 7 grams of protein per dose sounds almost comical to me. Is anyone experienced in the art and knows whether scale-up to literal tons of protein is even feasible?

    1. metacelsus says:

      I know subtilisin is produced by the ton for laundry detergent, but making GMP antibodies by the ton would certainly be extremely expensive.

      1. Mammalian scale-up person says:

        Opex + cost of goods runs about $700-1000/gram at this scale. A lot of that depends on resin capacity in the purification steps, chromatography resin is our most expensive consumable by far.

        Capex is a different matter and highly variable based on site selection and what resources a company already has. Can be anywhere from $300mio to $800mio, depending on if you already have some real estate and whether it needs site remediation or utility support (for example wastewater pretreatment, power generation or substation on site), how much automation you will implement and whether you are developing new code or copy/pasting from another facility, how much new technology you’re trying to implement (can result in long term savings but needs additional validation), what kind of pricing you can get on long lead equipment, who else is doing construction nearby and driving up your construction escalation costs, surprise steel tariffs…

        1. RLT2028 says:

          Your posts are always so informative, thank you.

        2. Anon says:

          Great, thank you for the detailed answer!

    2. Yas says:

      There are “protein powders” with less than 7g of protein content per scoop.

    3. Mammalian scale-up person says:

      The internet ate my post, but: yes. Several such facilities exist. The utility and water demands especially can be very large, and hiring a few hundred skilled biotech folks isn’t easy, so site analysis is critical. They take 2-3 years to construct after permits are issued if you’re copy/pasting another facility design and your automation code, 3-5 if you’re starting from nothing. However, single-product facilities are a huge business risk and expect the investment to be amortized over ~20 years; it wouldn’t make much sense to build a single-product facility for something that could feasibly have a vaccine in 5-7 years. They would either build with the intent to repurpose as needed or design some flexibility in for multiproduct operations or both. From a facility design perspective we would simply over-size the process tanks or get extras that would sit idle, and ensure there was plenty of additional space left as shell for a Phase 2 buildout when the original mAb is outdated by the vaccine.

      Here’s one that was recently built in Ireland:
      Here’s the renovation of an old Genentech building:

  7. A Nonny Mouse says:

    Regeneron version is about to start a 2000 patient trial in the UK.

    Meanwhile, it seems that the Imperial vaccine isn’t producing enough effect at the doses that it has been given at. One would have thought that, after the first 17 volunteers, they would have had sufficient information to move forward wit the next 300 (3 differnt doses).

    1. Valdis Andersons says:

      That’s interesting about the ICL vaccine. I think they are trying the self amplified mRNA type. They got good results in animals, haven’t seen any data from humans yet. Is there a link you could provide by any chance? I would be very interested in reading up on their findings.

      1. A Nonny Mouse says:

        They have sent out letters to the 300 people in the 3 dose leg of the trial, apparently.

        “…….In a letter sent to the 300 participants in the COVAC1 trial, researchers wrote: “There is a concern from the few initial results that we now have that the immune response may not be as strong as was hoped. So we need to explore the possibility of using higher doses……”

        I will speak to my daughter tomorrow when she returns for her follow up on Monday (she is one of them).

        It seems that they are recruiting 78 more people for a larger dose study.

        1. Valdis Andersons says:

          Thank you very much for the response, that’s very informative. Personally, I hope it really is just a dosing problem and not something more fundamental in the design of the vaccine itself.

          The saRNA technology for me is very fascinating as it would allow for minuscule dosages to be highly effective making production of the actual RNA less of an undertaking. One could go from thousands of kilograms in a production run to maybe tens of kilograms per run for the same dose count.

          1. A Nonny Mouse says:

            They have been looking at 0.1, 0.3 and 1 microgram, which isn’t enough for anti-body generation to any extent!

            They are going to look at 2.5, 5 and 10 now. The current cohort has been offered a third booster dose (higher amount to be decided) but my daughter has had to refuse as the follow ups after that would impact on her exams (150 mile journey, now).

  8. Barry says:

    Still missing is any evaluation of the pneumonia. Are mAbs given i.v. addressing the infection on the lung surface at all? Are these patients still infectious? Such a mAb may reduce the hospitalizations, stroke/coagulopathies and the myocarditis. But the study’s under-powered at best.

  9. Marko says:

    What was the placebo ? Unless it was non-specific gamma globulin , these results don’t do anything for me. Give a bunch of mildly ill patients an infusion of 3-7 grams of ANY old plasma protein – gamma globulin , albumin , even a MAb against a COVID-unrelated antigen – and you might see a reduction in hospitalization like this if compared to those receiving just a saline infusion.

    1. David E. Young, MD says:

      No, you need a saline placebo. If you have something else, and the treatment arm does better, the FDA might think the reason they did better was that the control arm (albumin, gamma globulin, etc) did worse and take the company to task for using such a control arm.

      If you think that Albumin shortens hospitalization for Covid, then propose a RCT to prove it.

      1. Marko says:

        Better tell that to the Oxford folks , who’re using a meningitis vaccine as placebo in the ChAdOx1 trial.

        I think it’s mental masturbation to assume the immune system is ONLY responding in a positive way to the very tiny part of large protein that you’ve spent $millions fiddling with , especially in the context of a novel coronavirus. Run a saline arm if need be , but also do a proper control.

        1. David E. Young, MD says:

          I’m not sure that I would make that choice of the “non-therapy arm” but you are right, they use a meningiococcus vaccine in UK and Brazil. In the US, the placebo arm is saline.

          1. Harvey 6'3.5" says:

            And using another vaccine makes sense to me, because if some of the effect of the vaccine is due to stimulation of the innate immune system, then hopefully use of another vaccine as placebo will capture that effect and make the results more robust.

            As a side note, it would be interesting if someone would track people receiving flu shots against a reasonable control group to see if vaccination in general reduces covid rates slightly (you can’t really compare against the general population because people getting flu shots are probably different in their habits).

  10. Calvin says:

    So basically this doesn’t work. It’s a dog’s dinner. My reading is that while they are seeing a viral load reduction it’s not dose dependent which means the viral load drop is small. Which is why they then have to pool the clinical endpoints to see reduction in hospitalization etc.

    What this tells me is that he antibody needs to be given much much earlier in the infection. Which makes me worry that these antibodies are all like the RSV antibodies which have to be given prophylactically to see any efficacy. Given that, like RSV, they hit fusion and so viral entry, this is maybe no a surprise. I’d kinda hoped that since COVID-19 looked systemic, more like Ebola than RSV, we’d see a Ebola-like outcome rather than a RSV outcome. Pity. So if it’s not give before peak viral load not much happens.

    PK will play a big role here though which I have not seen reported, so maybe it’s just not over the IC90 for long enough as well.

    Lilly appear to be continuing and obviously they have more data, but given the way they are trying to make the data look positive by cutting it in lots of way, and not appearing to worry about the lack of dose response, I think this looks unlikely to work. Pity. But probably a very handy tool antibody to help us refine PK/PD and understand prophylaxis versus treatment.

    1. Barry says:

      Covid 19 hits more than lungs. It may be that this mAb in the plasma compartment will reduce myocarditis, strokes, other coagulopathies…But they don’t report a reduced viral load on the respiratory tract, or that these patients are less contagious.

  11. TB12 says:

    Can someone educated me on Ab8? The media seems to be overblowing it.

  12. Bill says:

    Dr. John Cooper includes a section n Ab8 in this video:

    His comments are directed to the public more than the professional, but he includes links to original sources.

    1. TB12 says:

      Thanks! 14 minute mark for all those interested as well.

  13. Bill says:

    Oops, make that Dr. John Campbell

  14. Philip says:

    I am going to keep harping on this until it is fixed. Any antiviral therapy trial for COVID-19 that does not start treatment very soon after infection is doomed. OK, not doomed, but in very bad shape.

    If you wait until after symptoms have appeared, you have waited too long or very close to too long for antivirals to do much good. If you are going to do an antiviral trial, you must include at least twice weekly testing, with daily testing being best. The $5 Abbott antigen test would be a great one to use for a trial. Pick high risk places, such as prisons, school staff, meat packing plants and a few other places for subjects. Test the subjects as frequently as you can. When somebody tests positive with the cheap antigen test, test again with RT-PCR and record the CT values. Start treatment ASAP.

    1. Marko says:

      Agreed , but it doesn’t just apply to antiviral trials , it also applies to vaccine trials. For purposes of obtaining vaccine-induced herd immunity , we need to know the difference in infection/infectivity between the active vs. control arms. Measuring differences in disease severity , which is basically what the current trial designs are set up to do , only gives us a partial picture.

      If we’d had a Warp Speed program on rapid antigen tests from day one , by the time of trial enrollments we could have given everyone in the vaccine trials enough test strips for twice a week testing , then if positive , directions to come in for PCR , as you suggested. We’d be getting a whole lot more information out of the trials than what we’re getting now.

  15. Parasoxical says:

    Unusual Features of the SARS-CoV-2 Genome Suggesting Sophisticated Laboratory Modification Rather Than Natural Evolution and Delineation of Its Probable Synthetic Route Yan, Li-Meng, Rule of Law Society & Rule of Law Foundation; Kang, Shu; Guan, Jie; Hu, Shanchang
    Part of their thesis is that the bat virus that Covid supposedly evolved from is not confirmed in nature but only is the property of a military institute, so the bat virus was a cover story. Also that Covid matches other viruses too exactly at some points and is too shelf ready to attack humans, for it to have evolved naturally. The authors say it was developed in a Wuhan lab. I guess this is why Trump likes to call it Wuhan virus. A Shanghai lab that reported in January that it was a synthetic virus was shut down the next day and never reopened.
    Supposedly their paper has been already debunked.

      1. Parasoxical says:

        Makes a good general case for the way viruses evolve but doesn’t seem to take up and confront the Li Meng claims specifically.

    1. eub says:

      ‘Published’ by an organization originally chaired by Steve “flood the zone with shit” Bannon, and funded by the billionaire whose yacht he was arrested for the fraud charges on. FYI.

      As far as the content, see Carl Bergstrom.

      1. Parasoxical says:

        Looking for what Carl Bergstrom says about natural vs engineered SarsCov2, top hit is Twitter Apr 16
        “There is strong evidence that the #SARSCoV2 #coronavirus is NOT an engineered bioweapon.
        That said, it’s important to be upfront that we do not have sufficient evidence to exclude entirely the possibility that it escaped from a research lab doing gain of function experiments.”
        hmm. Not exactly a devastating rejoinder

        1. DrivingBy says:

          >>“There is strong evidence that the #SARSCoV2 #coronavirus is NOT an engineered bioweapon.
          That said, it’s important to be upfront that we do not have sufficient evidence to exclude entirely the possibility that it escaped from a research lab doing gain of function experiments.”
          hmm. Not exactly a devastating rejoinder<<

          "Devastating rejoinder" is generally not how science works. The last sentence adds rather than subtracts credibility.

          1. Churlish says:

            Strongly agree with DrivingBy. Not jumping to absolute conclusions shows that the person talking is thoughtful about the evidence available.

            It’s difficult to conclusively prove that something isn’t true. For example, it’s difficult to conclusively disprove that there isn’t an invisible unicorn living on the moon. I’ve heard a lot of people talking about that invisible moonicorn.

  16. Marko says:

    Another crummy outcome on a convalescent plasma trial , from India :

    Results: Between 22nd April to 14th July 2020, 464 participants were enrolled; 235 and 229 in
    intervention and control arm, respectively. Composite primary outcome was achieved in 44
    (18.7%) participants in the intervention arm and 41 (17.9%) in the control arm [aOR: 1.09; 95%
    CI: 0.67, 1.77]. Mortality was documented in 34 (14.5%) and 31 (13.5%) participants in
    intervention and control arm, respectively [aOR) 1.06 95% CI: 0.61 to 1.83].

    Interpretation: CP was not associated with reduction in mortality or progression to severe
    COVID-19. This trial has high generalizability and approximates real-life setting of CP therapy
    in settings with limited laboratory capacity. A priori measurement of neutralizing antibody titres in donors and participants may further clarify the role of CP in management of COVID-19.

    Not a great trial , as the patients had higher average neutralizing Ab titers than the donor CP used , similar to what happened in the Dutch trial that was shut down prematurely.

  17. Barry says:

    It does reinforce the conclusion that circulating IgG is not the only relevant defense here.

  18. FoodScientist says:

    They probably stored the 2800mg dose in galvanized steel buckets and some zinc leached into it….

    1. TabeaK says:

      Cute. Recombinant antibodies for injection are stored in glass vials.

  19. Given regulatory approvals and if financial limitations were no object, what would be the lead time till the first volumes of doses are available off the line, and how many doses would that be? And then what kind of month-on-month growth in production could be expected?

    1. Mammalian scale-up person says:

      Lead time from when? It depends.

      Backwards timeline:
      -Full production-
      Initial commercial thaw to first production batch: 45 days
      PPQ batches: 4 – 6 months
      Engineering runs: 3 – 6 months
      Media holds / sterility checks and environmental qualifications of space: 1 – 2 months
      I/O Q Commissioning: 3 – 6 months
      Long lead equipment delivery: 18 months for bioreactors – – – – Concurrently, building construction and site prep: 12 – 18 months
      Equipment drawing approvals: 3 – 6 months, if you do not already have drawings you are copy/pasting
      Process development for an established platform: 3 months
      Cell line development: 3 months
      Sequence generation and verification: 1 month

      Not included: permit wrangling, site remediation, fancy architecture requirements, new automation and eBR code development, utility substations, traffic surveys, hiring and training limitations, escalation time to account for labor shortages…

      1. Mammalian scale-up person says:

        Note, Process Development has already happened by the time a Phase 2 trial is complete, for the most part. Stability data collection runs concurrently with clinical trials Phase 1 – Phase 3. We don’t start considering new facility build-out until something is already in Phase 3 and has a high likelihood of success, and the engineering, architecture and design work typically take 6 – 9 months to work out even if you are doing something fairly simple in an established commercial area with plenty of support for biotech construction. This is a generic overview of critical path activities.

        Also note: there is NO month-on-month growth in a developed and filed process with a BLA, as a rule. Zero. Nada. In order to do so, you effectively have to build a second facility in parallel. You cannot make any process changes for slow incremental improvements, the whole point of a BLA is that the process is defined forever. I have tried to do incremental improvements and they are very, very difficult and if you are lucky enough to be able to do it with only major change controls and no re-filing, it is because the facility was built out of paperclips, prayers and chewing gum in the first place.

        1. Karl Zawadzki says:

          Mammalian scale-up person, your comments are an education. Thanks so much for posting!

          1. TLR789 says:

            Ya dude, I am curious what his background is without giving away his identity

          2. Indeed, extraordinarily illuminating; thank you for sharing your experience Mammalian Scale-up.

        2. Daren Austin says:

          You left out the human bioequivalence studies at every big process change point.

          1. Mammalian scale-up person says:

            Left out many things which happen concurrently and are certainly deal-breakers but tend to be less *exquisitely* time sensitive – they MUST get done by X time, but there’s less hard and fast “start by time 1, must be completed by time 2 or the whole project goes to heck”. Stage-gate reviews, assay development and qualification, supplier audits and qualifications, design and qualification and extractibles/leachables of single use materials, storage vessels and packaging materials, QC lab build-out, CMC binder assembly and submission, final fill system qualification, process intermediate hold time fine-tuning and addition of heat exchangers as needed, cGMP training programs implemented and onboarding employees trained, documentation systems established and qualified, logistics systems established with track and trace functions and freight stability testing, official label and package insert blessing, process and formulation patent filings, pre-inspection audits, cleaning and sterilization cycle development, PAT loop tuning, building management systems and AHU delivery and installation (also can be long lead, there was a component issue about two years ago and we couldn’t get AHUs for several months)…

            Many of these things, an established company with other facilities already up and running can leverage their existing systems: they already have supplier relationships, a full regulatory and documentation staff, facility engineers, validation methods and family groupings, training methods and plenty of support staff; it’s a matter of getting more and fitting them into an existing business structure, not something that has to be created from nothing. The parts that you have to create from nothing: new building, new equipment, new process, etc, all of which are cascading and dependent on the previous thing being complete and correct, are more painful.

            For in vivo bioequivalence specifically in mAbs: we are usually pretty confident about these because we can do peptide mapping and confirm the posttranslational modifications are the same with various mass spec and bioassays. It’s when the cell line is changed, that bioequivalence may be in doubt, as immunogenicity of rodent glycosylations is a known issue. For non-mAbs there are definitely more questions around bioequivalence, it’s just for mAbs in particular we don’t worry too much as long as the N-terminal sequence and glycosylations look OK.

  20. Marko says:

    Praise for transparency by Moderna because they released their trial protocol should perhaps be tempered. The Moderna CEO is being called out on twitter for not disclosing that they had received a FOIA request for the information weeks ago. Rather than foot-dragging on the FOIA, they may have decided it was better for PR purposes to release it now.

    The Pfizer protocol release was probably prompted by Moderna’s action. I’d expect others to follow suit shortly.

  21. Marko says:

    Interesting thread about recent studies showing that 10% or more of critical cases of COVID-19 seem to be due to patients having auto-antibodies to Type I IFNs. This might be a potential target for anti-idiotypic mAbs. Another possibility could be some sort of therapeutic induction of tolerance to IFNs :

    1. Marko says:

      More on this. Raises the question about what this might mean for convalescent plasma usage. At the least we should start screening new donors and any stored CP for autoantibodies ASAP :

  22. J N says:

    As long as people are still contributing to this thread:

    This “tiny antibody” sounds cool, especially if it results in smaller doses and non-infusion administration … but … in order that we don’t readily breed a virus with immunity to it, don’t we want at least one somewhat different, similarly effective and hopefully also tiny variant to administer with it?

    1. TallDave says:

      intriguing, hope we get more trials

      would seem to solve some of the reported delivery issues with mAbs

      good point on mutation, might need a cocktail to be commercially useful if the virus can mutate away from that target… unless being a fragment it somehow applies to multiple targets that rarely mutate together or something, seems unlikely but I’ll have to read more

      but no idea what manufacturing capacity is possible or in what timeframe — a lot of really good products may arrive to the market just as the pandemic dies out, or even well after

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