Why do you need a test before you have an third infusion? If you use alemtuzumab read on
So now you know the story that we have generated assays to detect alemtuzumab- specific anti-drug antibodies. Today, I give you the next and new installment of some work done by a Barts Medical student using the Technology invented by DrAngry. They had made the Globody reagent during their lab project, but came back in the summer holidays to do more lab work.
Now I told you we did not have any people that completely failed to deplete white blood cells after repeated samples at Barts MS, however at a meeting in Scotland, I was blabbing about stuff to alemtuzumab users and there we met a group from Wales.
Diolch i bobl Cymru. What an amazing resource. A big thank you to our Welsh Collaborators, who had the forsight to set up this resource. They have been collecting samples for ten years. They said that they had samples of bloods from people who had had at least three courses of antibody. We could test them…..on one condition!
We would not know anything about the bloods, or the clinical course of the the individuals, every thing was anonymous and unknown. It would all be done blinded. The group from Cardiff selected the samples from the Welsh Neurosceince Tissue Bank and they sent about 200 samples of blood. Its turned out that this was from repeated samples from about 30 individuals, 32 to be precise, who had had at least 3 courses of antibody and samples taken for over ten years. When the code was cracked, the results I think were amazing.
There were a few people who had given blood before dosing with alemtuzumab. They had a background of level of about 700 light units in the assay in comparison to the maximum recorded in the individuals with MS with an average of over 1,200,000 light units and over 90% showed a positive response. To put this in perspective about if we look at the maximum alemtuzumab level possible after infusion and gave 20 times more anti-alemtuzumab that level was about 20,000 light units.
If we looked at the whole population then there was no influence on drug-induced depletion for the first three cycles, but we could see individuals (10-20%) who were failing treatment and importantly it seems we could predict people who were going to fail treatment.
However to be fair, fifty percent of people needed no further treatment and most had been followed for at least 5 years and a number over 7.5 years. This confirms that reported by the Cambrige group that with three cycles of treatment about 75-80% of people get very long term benefit. So alemtuzumab is a good drug. I have never questioned that, but we can make it safer.
Our study says that whilst a drop in lymphocytes does not indicate who will succeed and who will fail, if you do not deplete it looks like you are at risk of disease activity. This is not surprising as only a small subset of cells in the blood will be important. But if you do not deplete this indicates the drug is not working!.
Therefore, it is important you check your depletion of cells so look at what happens one month before infusion and compare this with one month after. Neuros are often too busy and may not do this, particularly as they have been repeatedly told they are unimportant and they are looking for a drop in platelets as an indication of a side effect. Remind your MS nurse to do this….it may save you a relapse down the line. The question is how best to define the cut-off. Is it not depleting below the lower limit of normal (1 x 10*9 cells/L) or a percentage drop. If we applied the later criteria all people in cycle 4 would be red and all of these people exhibited disease break through.
Now we looked at the anti-drug antibody responses. If we looked at the pre-dose, anti-drug response we could perhaps predict the post-dose lymphocyte depletion response. This may suggest that we could spot about 20% of people who will fail treatment. With more work we may be able to improve on this.
In the Welsh cohort, we found about 10-20% of depletion failures (remeber this is a select population and that only represents about 40-50% of the starting population), most but not all could be linked to anti-drug responses. There are other explanations, so more student power needed. However, it suggests that a test costing a few quid is worth it to protect a futile treatment costing thousands and I was shocked to see the number of futile treatments notably in some people from the CARE-MS extension trials.
There you have it bench to bedside….student power and the brains of DrAngry
We now have a test for any person needing two or more cycles of alemtuzumab. This is available to our and other neuros and we have already told the company about our data months ago when we first reported it in Novemeber. Why weren’t they interested?
You know the rules of Fight-Club
It seems rule number one of Pharma Club is dont’ admit there any problems with your products, you can guess what rule number two is.
Hopefully, they will now make this or other tests available to you. They have had one for years, its part of the drug development process.
You should ask to be tested before you get your next course of treatment after the first course. You can get your neuro to contact us! We have the technology. Just remember in the past-study reported months ago, the sample we tested was sent overnight by post (antibody is very stable and so doesn’t need to be sent on ice) from the USA. By the time they woke with the time delay we had the results. If we can get some intrastructure, as it currently needs hands, to run this, but DocA knows how to automate it. Come talk to DrA.
Read the story
The Irony of Humanization: Alemtuzumab, the First, But One of the Most Immunogenic, Humanized Monoclonal Antibodies.Baker D, Ali L, Saxena G, Pryce G, Jones M, Schmierer K, Giovannoni G, Gnanapavan S, Munger KC, Samkoff L, Goodman A, Kang AS.Front Immunol. 2020 Feb 14;11:124. doi: 10.3389/fimmu.2020.00124.
Stay tuned. There will be The irony of humanisation Part VII….when we can get back in the lab to complete the work.
Can this technology be applied else where? Of course it can.
Which badge will you get?
So you may have seen the picture building below of a legless tortoise chasing a hare…You saw it appear in real time from the wheels going on to squashing a bunny or two. This was DrAngry eventually being allowed into the lab (long story) to apply the technology, used in the anti-drug response reported here, for COVID-19. This was Triska’s project.
Within one week, in fact a few working days, DocA had made the reagents and enough to test all NHS staff in the whole of the UK (1.5 million), plus all staff and students from Queen Mary University of London (32,000) with abit to spare. With abit of paper work and planning, this could have been 64,000,000 tests in one go (made within a day or 2..but taking time to purify) for all of the UK with the help from the Chemistry department. This can be done using equipment that is available in every Country, no matter how resource poor they may be. So remember this when the next virus or variant of the virus appears
However, pharma has got there now, after 4-5 months, but I suspect there will be a few eligible people…not getting their “Had It” badge as it is not as good as we are led to believe. Therefore, your best way of getting an “Had It” badge from DocA is to sign up to the COVID-19 MS register (CLICK). More on that story later.
We have to ask why hasn’t this been made available? We now have to do a propective study and collect bloods to predict what will happen, however, sadly with the bad press that alemtuzumab has attracted recently, it is getting harder to get the samples. Hopefully we can make alemtuzumab that bit safer.
Detecting and predicting neutralization of alemtuzumab responses in multiple sclerosis
Gauri Saxena, James M. Moore, Meleri Jones, Gareth Pryce, Liaqat Ali, Georgia R. Leisegang, Vivek Vijay, Samantha Loveless, Neil P. Robertson, Klaus Schmierer, Gavin Giovannoni, Sharmilee Gnananpavan, David Baker, Emma C. Tallantyre, Angray S. Kang. Detecting and predicting neutralization of alemtuzumab responses in multiple sclerosis. Neurology, Neuroimmunology, Neuroinflammation 2020.
Objective: To test the hypothesis that anti-drug antibodies against alemtuzumab could become relevant after repeated treatments for some individuals, possibly explaining occasional treatment resistance.
Methods: Recombinant alemtuzumab single-chain variable fragment antibody with a dual tandem nanoluciferase reporter linker was made and used to detect binding anti-drug antibodies. Alemtuzumab IgG alexa-fluor 488 conjugate was used in a competitive-binding cell based assay to detect neutralizing anti-drug antibodies. The assays were used to retrospectively screen, blinded, banked-serum samples from people with multiple sclerosis (n=32) who had received three or more cycles of alemtuzumab. Lymphocyte depletion was measured between baseline and about 1 month post-infusion.
Results: The number of individuals showing inadequate depletion of lymphocytes increased with the number of treatment cycles. Lack of depletion was also a poor prognostic feature for depletion and treatment failure following future cycles. Anti-drug antibody responses were detected in 29/32 (90.6%) individuals. Neutralizing antibodies occurred prior to the development of poor depletion in 6/7 individuals (18.8% of the whole sample). Pre-infusion, anti-drug antibody levels predicted poor post-infusion lymphocyte depletion.
Conclusions: Although anti-drug antibodies to alemtuzumab have been portrayed as being of no clinical significance, alemtuzumab-specific anti-drug antibodies appear to be clinically relevant for some individuals, although causation remains to be established. Monitoring of, lymphocyte depletion and the anti-drug response may be of practical value in patients requiring additional cycles of alemtuzumab. Anti-drug antibody detection may help to inform on re-treatment or switching to another treatment.
CoI. DrA has a patent on the Globody technology