Alemtuzumab.The irony of Humanisation. Part V

A

What have we been doing. So over the past week has been building up the story of alemtuzumab, the Worlds first Humanized antibody. However, it is the worst when it comes to anti-drug antibody responses.

The paper today argues perhaps why. So if you are taking alemtuzumab it is a must-read.

So you can sit down in you arm chair and have a good read. The paper is now online so click here , download, and enjoy

ProfGhas rose-tinted glassess, DrAngry has had MD look at the data through their Specs, what did he see?

You may say that we are being anti-pharma. We are not!

We just want to try help a few people who will suffer the consequences, if we don’t say and do anything. Because there have indeed been some people in that situation! Importantly we are talking about people and not statistics

The irony of humanization: Alemtuzumab the first, but one of the most immunogenic, humanized monoclonal antibodies. David BakerLiaqat Ali, Gauri Saxena, Gareth Pryce, Meleri Jones, Klaus Schmierer, Gavin Giovannoni, Sharmilee Gnanapavan, Kathleen C. Munger, Lawrence Samkoff, Andrew Goodman, Angray S. Kang.   Froniters Immunology Front. Immunol. doi: 10.3389/fimmu.2020.00124

Alemtuzumab was designed to reduce the immunogenicity of the parent, CD52-specific, rat immunoglobulin. Although originally marketed for use in cancer (Mabcampath®), alemtuzumab is currently licensed and formulated for the treatment of relapsing multiple sclerosis (Lemtrada®). Likely, due to its history as the first humanized antibody, the potential of immunogenicity of the molecule has been considered inconsequential, and anti-drug anti-drug antibodies (ADA) responses were similarly reported as being clinically insignificant. Nonetheless, despite humanization and depletion of peripheral T and B cells, alemtuzumab probably generates the highest frequency of binding and neutralizing ADA of all humanized antibodies currently in clinical use, and they occur rapidly in a large majority of people with MS (pwMS) on alemtuzumab treatment. These ADA appear to be an inherent issue of the biology of the molecule and, importantly, the target, such that avoidance of immunogenicity related-effects may have driven the dosing-schedule in clinical practice. At the population level this enables the drug to work in most pwMS, but in some individuals, as we show here, antibody neutralization appears to be sufficiently severe to reduce efficacy and allow disease-breakthrough. It is therefore imperative that efficacy of lymphocyte depletion and the anti-drug response is monitored in people requiring additional cycles of treatment, notably following disease breakthrough. This may help inform whether to re-treat or switch to another disease modifying treatment

Therefore, if you are recieving alemtuzumab or consider using this, please read this post. This is about people who stop responding to alemtuzumab, show disease actvity and accumulate disability.

Can we guess which people that will occur in? I think we can, at least to some extent . Sure we need more data.

Remember the Astro Merid Huian Post relating to “Class action” film when the car with the indicator (blinker) over the petrol (gas) tank that exploded when the car was rear-ended (hit from behind) whilst turning left. The manufacturer kept quiet and rather than fix the car, they were thought it was cheaper to deal with the families of the people blown up. Cheaper for them, but not so great if you are the person vapourised. I guess it is worse is to be vapourised and get no compensation:-(

The manufacturer’s do not think it is a big issue. It isn’t unless you are one of the affected individuals and then it’s a big issue, just like an Astro Meridian would be important. We asked for the data but you can select to do the analysis in such a way as to minimise the issue we were asking about. This is what was done.

ECTRIMS 2018 poster 611.

The manufacturer have data on individual pre-and post dose lymphocyte numbers and pre and post- dose binding and neutralizing antibody responses. In the CARE-MS trials there were about 800 people and about 250 people from the CARE-MS EXTENSION study where people got repeated doses of alemtuzumab. No data on the effects of neutralizing (inhibitory) antibodies in relation individual response has been presented.

I know I will take abuse from the Cambridge fan club and so be it Mr. Angry from Tunbridge Wells, but the whole point of this study is to try make alemtuzumab use safer and for the individuals who are not responding, they need to be switched onto something they do respond to.

So what have we done? If you have been following the story. The idea of humanised monoclonal antibody production was invented in Cambridge Alemtuzumab was designed to reduce human rejection of the rodent protein in the original antibodies. However, the irony is that alemtuzumab is probably the worse humanised antibody on the planet and when used in MS, virtually everybody that gets it makes an antibody response againt it.

Response over 2 years

Cambridge realised this and did a trial to get rid of them.

A novel strategy to reduce the immunogenicity of biological therapies.Somerfield J, Hill-Cawthorne GA, Lin A, Zandi MS, McCarthy C, Jones JL, Willcox M, Shaw D, Thompson SA, Compston AS, Hale G, Waldmann H, Coles AJ. J Immunol. 2010;185:763-8

Why would you do this if they weren’t a problem? Indeed, it is amazing what you can find on the internet.

A talk that never saw the light of day showing >30% (year 1), 70 % (year 2) and 100% (year 3), hardly 0.5% (year 1) and 26% (year 2) as in the phase II report. (They ignored anyone below the 2,000U/ml limit. Where did this limit come from and what does it mean?) , and there are people who stop responding?

https://www.e-i-p.eu/wp-content/uploads/2013/02/04_Alasdair_Coles_presentation.pdf

There are a few more examples that can be found on the internet of people who stop responding to alemtuzumab, one in the manuscript which made us think about the issue, which Genzyme allowed us to publish (Thanks to them for this. See we are not anti-pharma and have been telling them what we are up to). There is another nice study from Austria/Dresden that we know of, as it was presented at ECTRIMS, but it has never been published.

I also have to say I missed this one and thanks for Luis from the blog for bringing this to my attention this week.

Lack of CD4+ T cell percent decrease in alemtuzumab-treated multiple sclerosis patients with persistent relapses. Rolla S, De Mercanti SF, Bardina V, Horakova D, Habek M, Adamec I, Cocco E, Annovazzi P, Vladic A, Novelli F, Durelli L, Clerico M. J Neuroimmunol. 2017 ;313:89-91

If you look at P#1 and P#2 top row they deplete on first infusion dotted line but on the second infusion they don’t or repopulate quickly and within 12-18 month later they get clinical activity (arrow) So this may suggest something disappears for 2 to 3 years from first infusion. I wonder that that may be?…. They get another dose (dotted line) and they deplete poorly or repopulate quicky again suggesting the drug is not working and have another dose and again there is no big effect on depletion and you get disease break through. Now they have focused on the percentage of CD4 not changing, but as we have said working on percentages is not the thing to do as you need to look at absolute numbers. If the percentages have not changed other cells have depleted in the same ratio also. However, I would guess there is a good chance these people neutralised the response. What do you think? However, you go to the discussion and neutralizing antibodies are not mentioned, supporting the idea that people were not thinking about them. However, it shows people not depleting well on second cycle in the CARE-MS extension study. I know there are a few more than this but thats part VI yet to come. So can (luke & Alan) Sanofi please get the data ready.

How do you explain that ADA do not have a big effect.

When you think about it abit, the dosing schedule works to avoid the problems associated with the development of anti-drug antibodies. Not least because you have to wait a year before the next dose rather than give another bash of drug after disease break through. Why….I’m am guessing because it gives time for the anti-drug antibody response to subside. Is this a problem? We thought it would be for some people.

Incidently a referee (not mentioned in the referee list and likely not to be UK based..who tried to put the boot in not realising that the paper was part of a special issue on immunogenicity) said ADA weren’t part of the reason behind the dosing schedule. This means they were part of the decision process, conflicted, and therefore perhaps have integrity issues, if this was not declared before the review was accepted:-). Therefore, the company got incredibly lucky with the dosing schedule, which let’s face it, allowed the manufacturer to get a patent position on the drug giving it many years of extra market protection. However, I thought I had removed most of this suggestion from the text because but looks like we forgot the abstract….Ooopps.

Treatment of MS with CAMPATH-1H US20060844251

However, Anti Drug Antibodies was never part of the message about the role of alemtuzumab in MS and still isn’t (see above) from the company . Is this the Astro Meridian approach? Maybe, but it is just a “don’t admit or draw attention to any problems” approach indeed Rule number one of Pharma club is don’t talk about weakness…..Rule number two of Pharma club is…Don’t talk about weakness. Rule number 3 is yep you guessed it.

AAN 2013

To be honest, initially we were oblivious to all of this until we saw the trial report. It was there in the blurb in the label so the Neuros just had to read that. However, we were told that neutralizing antibodies weren’t important or didn’t exist and we were told that lymphocyte numbers bear no relationship to lymphocyte numbers, so anti-drug antibodies never entered peoples minds. So our molehill was made. Ask your neuro next time you have a dose and see if they they know about neutralizing antibodies? I asked a few and they knew nothing, prompting our activity.. Yep it means they don’t read the blog..or more. But that was a motive to publish

When we think about it there are many reasons why alemtuzumab is it’s own worse enemy for creating anti-drug antibody response. It is a problem of the dose, the dosing schedule, the antibody and the biology of CD52.

It is the biological “Perfect Storm” in relation to anti-drug antibodies. Have a look in the table below. The potential issue is in red, the issues are in black.

If this picture is not clear, don’t worry, others so too that’s why it was cut from the paper. Have a read of the paper and fear not there is another paper (Part VI) being reviewed that will explain this further. We will post this when it comes online.

Whilst lymphocyte numbers may not relate to disease activity, lack of depletion of lymphocytes suggests the drug is not working. So check your bloods after alemtuzumab as your neuro may be too busy to take notice

Luckily in the BartMS team we have not seen a person who completely stops depleting their whte blood cells and stops responding to alemtuzumab, but we expected this to happen, especially once the EMA approved the third and forth courses of alemtuzumab. This is why we generated the anti-drug antibody assays that we have told you about.

But when we were preparing the manuscript we got a call from our American co-authors about a person who stopped depleting their lymphocytes and failed treatment. We got the blood after 5 cycles of plasma exchange, to try and remove pathogenic antibodies, and a course of steroids, to reduce inflammation. They had a lot of anti-drug antibody response even after their serum was replaced 5 times with 800,000 light units of antibody and a potent neutralizing response, which to put it in prospective, is over 50 times the critical level associated with lack of activity.

This person is not unique (Part VI), but the case report will be at the AAN 2020, Good job their neuro was informed and on the ball.

How common is this? I am sure Cambridge and Sanofi will have much to say and our paper may allow them to share their experiences, even it is simply to modify what we have suggested. Importantly, is this seen in the CARE-MS trial extension data? Maybe time to let us look, as it probably needs to be done independentently to be credible. We need to look at individuals, which will show how many people fail treatment (it won’t be a big number I suspect), and not the population, which will show nothing.

This latter view is already published and our data does not disagree with this, but the individual is important.

CoI: Multiple DrKang has filed patents in relation to the anti-drug assays

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MouseDoctor

13 comments

  • I have nothing to say but am commenting to make sure I am subscribed to follow-up comments on this exceptional post!

    (Its time for a Subscribe Button purhaps?)

  • COI – I’ve had 2 round of Alemtuzumab some 13 and 12 years ago. I remain relapse free, no MRI activity and stable EDSS. Cambridge are the bees knees in my view.

    I’ve read through your various posts – you’ve been busy. My thoughts:

    – have you contacted the Cambridge team for their thoughts?
    – we must no forget that this is a very effective treatment for most people. Good monitoring should detect breakthrough disease and a decision will then need to be taken on what further treatment is needed.
    – while I admire your research into Alemtuzumab I also have to ask why you have spent time on this when effort could have been focused on identifying effective and safer DMTs. Alemtuzumab is an old drug and probably doesn’t have a long future in the MS field.

    I know you’re not a doctor but if you were diagnosed with rapidly evolving RRMS what, from a researcher point of view, would you choose? You have pretty much concluded that the CRAB drugs are a waste of space.

    I wish the researchers / pharma could develop drugs that just work. What we have now in MS is a system where researchers identify possible drugs, pharma test them, if effective government licenses them, and then researchers spend decades reviewing all the trial data and identifying problems, government then takes away the licence or changes the labelling….. It’s a big merry go round that keeps lots of people employed.

    • Happy that you have had good experience about 75 percent do from 2-3 courses. However, spare a thought for the person with six courses, 4 needless disease episodes and 3 points on for EDSS.

      We were one of the heaviest users of alemtuzumab and given the NHS decision to approve 3 and the EMA to approve 3-4 courses. We saw a potential issue for some this case study developed because the person was not been tested.

      Contacted……yes. They were going to report neutralization. No paper has yet surfaced.

      Effective… Yes indeed, but this about a decision aid and importantly not monitoring break but predicting it before it happens.

      This will be clearer input next paper..

      We could have spent time developing drugs. These agents were made by undergraduate students as part of their lab projects. We try give them something interesting and achievable in 1-3 months. We have a few more to do. This work gave a paper to a BSC student, an MSc student and a medical student.

      Part of post marking surveillance it is important to monitor safety. As a consequence of this work I hope that monitoring will be developed, it’s all about safety.

      • Real-world monitoring and follow-up is essential also for evaluation of efficacy, given the careful pre-randomization selection common in clinical trials. I want things that work as much as anyone, but rational evaluation of what’s already available will reduce the chance of marginally effective drugs getting approved and complicating decision-making without appreciable benefit.

  • I also have to say I missed this one and thanks for Luis from the blog for bringing this to my attention this week

    🙂
    🙂

    Appreciate

    Coi: Its not only Hsct 😉

  • Hi !
    great work ! Thank you all in advance for continuous research regarding MS .

    I have MS and i started Alemtuzumab in 02/2019 (18/22 February), previously i was on Natalizumab (from march/2008 to November 2019, with high level of lymphocytes in the blood)
    R1 started march 27th lymphocyte countn (25th march) dropped to 29/ul (23.3% CD4, 22.9% CD8), then they slowly raised to 460 (January/2020).
    Started R2 in 17th February, lymphocyte count dropped to 19 and is slowly increasing – 70 in April, 180 this month)
    According to the study conducted in Bart School I´m not included in the percentage of pwMS treated with Alemtuzumab that didn’t deplete lymphocytes, am i wrong?

    Thank you all

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