Dr Angry crank up the Machine…another project.

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DrAngry is a bit of a boffin and has been making anti-drug antibody assays. We have a paper about to arrive on the anti-drug antibody (ADA) response of alemtuzumab. It is the “poster-girl/boy” when it comes to ADA as it causes then in so many people. It busts the myth that making a humanised antibody makes things less immunogenic (rejected by the immune system). It can cause about 60% of people to make an ADA within the first month when there are no T or B cells. So why not an anti-COVID response? Now we made these reagents using “student power” and they have now refined the technology that we can make a new one as fast as you can say “What is the Sequence“. These are not that hard to find:-)

sequences of CD20-specific antibodies

Today we see a company moving a step nearer moving yet another anti-CD20 antibody towards MS.

We have ocrelizumab a humanised antibody which has mouse bits and is 95% human. This replaced rituximab that had more mouse bits and a human tail and is what is called a chimeric antibody. Ofatumumab is a fully human antibody that will be injected into into the skin once a month compared to the ocrelizumab, rituximab and now ublituximab that get infused every 6 months.

A phase 2 multicenter study of ublituximab, a novel glycoengineered anti-CD20 monoclonal antibody, in patients with relapsing forms of multiple sclerosis. Fox E, Lovett-Racke AE, Gormley M, Liu Y, Petracca M, Cocozza S, Shubin R, Wray S, Weiss MS, Bosco JA, Power SA, Mok K, Inglese M. Mult Scler. 2020 Apr 30:1352458520918375. doi: 10.1177/1352458520918375. [Epub ahead of print]

Ocrelizumab is more pokey than rituximab because it kills B cells by antibody dependent cellular cytotoxicity (ADCC). So let’s make another antibody that works by ADCC ….So ublituximab is born.

However, chimeric antibodies have a bit too much mouse or rat protein and they cause ADA. One selling point is that ocrelizumab is less immunogenic than rituximab and presumably ublixtuximab. This seems to be the case as rituximab make ADA in 15-25% of people so they stop working, ocrelizumab causes ADA in less than 1% of people. Is ublixtuimab a mistake is it more immuneogenic than ocrelizumab?. There was no mention of ADA…So I shout “DrAngry crank up the machine we have another project“. Let’s see how quick DrA can have one, from start to assay…I predict less than 4 days on a good day…Give us a call we can do your phase III….on a not so good day, definately less than 2 weeks. Any way this is for the future.

However, this difference is a bit of a myth as the humanised and human antibodies are immunogenic, especially if they have clumps. Ocrelizumab induces ADA in 20% of people if you drop the dose from 600mg to 20mg. The subcutaneous route is the immunzing route will there be a difference between ocrelizumab and ofatumumab? There will be no difference to start with as we know the data already but what happens over time…”DrAngray crank up the machine!” 🙂

Ublituixmab is infused over an hour. Is this a selling point, I wonder?. I think studies are being done with fast infusions with ocrelizumab maybe by the makers of ocrelizumab, but I think there are other studies, it is called the COVID-19 study. I heard they can shave 100minutes off some infusions to reduce time of people in hospital. Avoid it all together I hear you say take an oral DMT!

Now the other issue is where is the data on what happens to the memory and immature cells?. If ublizuximab is as pokey as ocrelizumab then you are going to have to wait a year or more for them to return. WIth ofatumaumab they are back within a short time of stopping…all important for the COVID vaccine. I can see the CD20 wars hotting up…Time for a review…”OK DrA I’ll crank up the machine. :-)”

On cost grounds there is another battle to be had: Experience with rituximab therapy in a real-life sample of multiple sclerosis patients. Bellinvia A, Prestipino E, Portaccio E, Razzolini L, Fonderico M, Fratangelo R, Tudisco L, Pastò L, Amato MP.Neurol Sci. 2020 Apr 29. doi: 10.1007/s10072-020-04434-1. [Epub ahead of print]

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