CD20 B cell therapy…In progressive animals


Anti-CD20 Disrupts Meningeal B-Cell Aggregates in a Model of Secondary Progressive Multiple Sclerosis.Roodselaar J, Zhou Y, Leppert D, Hauser AE, Urich E, Anthony DC.Neurol Neuroimmunol Neuroinflamm. 2021 Mar 2;8(3):e975.

Objective: Therapies targeting B cells have been used in the clinic for multiple sclerosis (MS). In patients with relapsing MS, anti-CD20 therapy often suppresses relapse activity; yet, their effect on disease progression has been disappointing. Most anti-CD20 therapeutic antibodies are type I (rituxumab and ocrelizumab), but within the unique microenvironment of the brain, type II antibodies (one that kills B cells directly) may be more beneficial, as type II antibodies exhibit reduced complement-dependent cytotoxicity and they have an increased capacity to induce direct cell death that is independent of the host immune response.

Methods: We compared the effect of type I with type II anti-CD20 therapy in a new rodent model of secondary progressive MS (SPMS), which recapitulates the principal histopathologic features of MS including meningeal B-cell aggregates. (This was done in adult humanized (hu)CD20 C57BL/6 mice, expressing human CD20 exclusively on B cells).

Focal MS-like lesions were induced by injecting heat-killed Mycobacterium tuberculosis into the cortex (outside of the brain) of MOG-immunized mice. Groups of mice were treated with anti-CD20 antibodies (type I [rituxumab, 10 mg/kg] or type II [GA101, 10 mg/kg]) 4 weeks after lesion initiation, and outcomes were evaluated by immunohistochemistry.

Results: Anti-CD20 therapy decreased the extent of glial activation, significantly decreased the number of B and T lymphocytes in the lesion, and resulted in disruption of the meningeal aggregates. Moreover, at the given dose, the type II anti-CD20 therapy was more efficacious than the type I and also protected against neuronal death.

Conclusions: These results indicate that anti-CD20 may be an effective therapy for SPMS with B-cell aggregates and that the elimination of CD20+ B cells alone is sufficient to cause disruption of aggregates in the brain.

So its amazing and we all made out of star dust..This seems to under pin the use of ocrelizumab in progressive MS, but says Obinutuzumab could be better. So the question now is whether there is enough antibody to do this in MS

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    • I think (a) Antibody does not get into the human CNS and (b) there are mechanisms that are not depenednt on B cells

      • That is obviously true.

        To clear disease in the CNS there is no question in my mind that we need to develop strategies for treatment that include combination therapies and an agent that can that can cross the intact blood brain barrier.

  • Eae its mouse model of relapsing disease its …Well not so good

    Eae its mainly a t cell disease and lymphocyte acumulate mainly in the spinal cord

    How can you recapitulate progressive disease in a mouse model?

    They inject heat-killed Mycobacterium tuberculosis into the cortex?

    What does this have to do with spms?


  • Isn’t it about time technology came up with a better mechanism that using sentient beings? Mice are affectionate creatures. Does anyone ever give them back any affection, or are they just seen as nonentity material?

    • I can’t tell by reading whether this is tongue-in-cheek, but I am increasingly bothered by the thought of the animals suffering for our benefit. Would love to know how petri dish cell testing can stand in for live animals.

      • When you’re dealing with the interaction of the most complicated organ in the body (central nervous system) and the second most complex (the immune system) as it pertains to MS, sadly, any meaningful cell-based substitute is still a long way off. This is compounded by the fact that most animal models are in no way realistic either.

  • Although this study was done in mice, and what the authors showed was impressive it begs a very simple question – does Ocrevus penetrate the BBB and do we have any data to suggest that it is true?

    • It will be 99% excluded and could be 99.9% there is plenty of data on antibodies getting into the CNS or rather having poor penetration.

      • Was it a typo ? You said ‘there is plenty of data on Abs getting into the CNS’

        I guess you meant plenty of data of Abs NOT getting into the CNS. Right ?

        SIZE is the biggest reason why the BBB penetration is impossible w ocrelizumab, ofatumumab, rituximab, etc.

        William Pardridge (UCLA), a serious proponent of why drug companies must heed the BBB properties to the hilt, to be successful, always writes about this topic in a big way.

        My suspicion on the mouse study is that the results will NOT hold up in clinical studies. As for mice being cuddly and cute, I agree and since human beings are the worst animal there is, we treat all comers – monkeys or mice – as disposable ‘objects’ in our journey to discovery land. Sad, but true.

        • Yes plenty of data that they do it badly. Yep To inhibit relapse the drugs dont neeed to get in CNS.

          I heard there is one consequence of COVID…all the monkies in the West have been used up for COVID research….Apparently there is an export ban of monkeys from China…so the drug testing companies can’t get the monkeys to do drug testing safety studies. Therefore there is abit of problem and means that you have to go to China to do the animal testing.

          • The drugs do NOT need to get into the CNS to reduce relapses. That is a given.

            My point is that they DO need to get into the CNS, after all, to get at the B cell follicles that set up shot in the subpial space, as part of the cortical lesions that are present even at the CIS stage. Cortex forms about 80% of the brain mass and while all of us focus on the white matter because that is what our 3T magnets pick up on scans, it is the cortex that harbors the disease, hides it well, and is responsible for the chronicity of the disease and if our drugs do NOT penetrate the BBB, how are we ever tackling disease that has ‘infiltrated’ and is impossible to reach ? It is sequestered . We can kill all the CD19/20 cells that we want and meanwhile there are studies that show that plasmablasts and plasma cells PERSIST and so one even wonders how we are producing the effect with the wildly successful CD20 depleting agents which is another topic, of course, not to talk about repopulating cells being MORE naive and transitional cells…….lot to ponder there, I think.

            Hence, this study that you had pointed out, seems to be working in a mouse model and my contention is that it cannot work in human clinical trials (one needs to list ALL the MAb failures in ALL neurological diseases including Alzheimer’s and it then becomes apparent that the common thread in failures has to do w the MAb molecular mass/size – trying to fit a tennis ball past a pinhole does not work) .

          • The study makes the suggestion that type II anti-CD20 are better than type I anti-CD20 and they use ritxuimab (type I) and GA101 (type II) These can induce cell death and so don.t need to kill by complent (which pokes holes in a cell where the antibody binds) or cell dependent killing that pokes holes in the cells onto which the antibdoy binds.

            However ocrelizumab is a type I antibody (Meyer et al. Br J Haematol. 2018 Mar;180(6):808) and others agree with this Mossner et al. Volume 115:4393. The type II antibody is Obinutuzumab (GA101), which is another Roche antibody. This is used in cancer in combination with other anti-cancer drugs. It can activate complement and killing cells also. Maybe obinutuzumab would be a better candidate to develop for progressive MS. It is abit more potent than rituximab….and so not surprising it inhibits microglia and astrocytes (this probably a down stream effect of being more effective at blocking lymphocytes) the however that can come with a down side of an infection risk

          • Agree that type I and II Abs are fundamentally different in that their interaction with CD20 is possibly different although they could be occupying an overlapping CD20 epitope. Clinical efficacy apart, some of their effects can also be demonstrated on cells in the innate immunity arm, viz, microglia/dendritic cells, macrophages, etc. My sense is that they work great peripherally and produce clinical efficacy #s, but they may not be geared to get into the CNS.

            Combination therapies are the way to go, I think – a small molecule (cyclophosphamide, Finglolimod, BTK inhibitors when they finally come around, etc) plus a peripheral B cell killer might be the ticket.

            The Pfizer team might have different ideas, however, and an mRNA product is probably in the works for clinical trials in MS ??

          • Your idea for B cells and combination therapy is something we have beeen saving. Cyclophophamide is definately a peripheral B cell killer

            mRNA for MS…I guess we wait if they take it forward

          • In the animal experiment the results can possibly be explained by a peripheral effect as you say but treatment was intially after the B cell accumulated. tennics ball through pinhole 🙂

  • Combination….anti CD-20 (kill the bad B cells), then short round of teriflunomide (naive B cells repopulate in the presence of antiviral), then cladribine to restart the immune system (cns penetrant).

    Then hopefully no more drugs and NEDA 🙏

    Anti CD-20 stopped aggressive inflammation in cervical spine, teriflunomide prevents EVB cell reinfection, cladribine gets into cns and removes bands. System restarted….without aHsct 🧐.

    • anti CD20 and teri (Roche and Sanofi) I doubt will happen, alemtuzumab and teri (both sanofi) could have been a possibility and was the basis of the iteri trial ut I suspect the moment has passed. If you have a depleter and the only way to repopulate is to proliferate, teri is anti-proliferative, will you get repopulation..need some animal studies to see what happens. If teri is such a good EBV killer and EBV is so important, why is teri not more effective? Cladribine gets in CNS and removes bands. I predict this will not be quick…I suspect it removes the niche supporting cells

      • “If you have a depleter and the only way to repopulate is to proliferate, teri is anti-proliferative, will you get repopulation..need some animal studies to see what happens.“…….I can give you one “human” data point…..yes. Circulating cd19 B cells can repopulate in the presence of Teri. Not sure what type or how the new repopulated cells act in a modified regulatory immune environment. However, Teri seems to keep the cd19 levels well below base line, which theoretically suggests a way to extend the benefit of a depleting agent.

        • With a depleting agent it is not necessarily keeping them down forever that is important I think making them different is the key. Eventually cells after alemtuzumab come back but importantly they are not the same cells

          • B cells that repopulate are naive and transitional. They there predominantly not auto reactive.

            For their numbers to come back to pre-depletion levels, it may be two years or more I believe depending on what you read and who the author might be. So why we give B-cell depleting drugs like clockwork is absolutely meaningless. It is the tail wagging the dog ! It depends on BSA, BMI, and many other factors play into this and some of the B cell depleting drugs need B cells to be eliminated in the first place! That is how
            they get eliminated and their half-life increases presumably with each passing infusion or dose.

          • I agree that the cells that come back are naive and transitional (immature) but not sure it is totally tru that they are not auto reactive. It has been claimed that over 50% could be autoreactive and we have suggested that their return in the absence of regulation is part of the reason why alemtuzumab induces so many different secondary autoimmunitities…there is a new one on haemophilia A in the last copule of weeks.

            Why we give B cell drugs like clockwork….maybe the neuros are like robots you wind them up and then they stop until you wind them up again when they inject:-)

            Excel point as you say the first doses of drug wipe out B cells subsequent doses you are giving drug when there is relatively nothing there to deplete. So the drug hangs round for a long time

  • I was going to ask this question in the Q and A but this might be a better place. Is there an element of HSCT that deals with what is going on within the CNS?

    • In a quick answer no. The treatments that clear the CNS dont really act in the CNS so you may leave what is in the CNS untouched. This can be see in post mortem when people surcome to HSCT-related infection. Some will say that cyclophophamide gets in the brain and I say yes, but it only will target dividing cells and the immune system does not lead to division. However it will removed the peripheral drivers that influence inflammation within the CNS. The microglia in the CNS have a very slow turn over, some will argue that they dont come from the bone marrow and would not be affected by HSCT

      • Thanks MD. So if the disease is still left to smoulder within the CNS, how can HSCT claim to tackle the degenerative element?

      • Thanks MD. So how does HSCT target the degenerative / smouldering element of the disease? Or is the answer that it doesn’t

        • In some people it doesnt you look in post-mortem brains of people who die for infection and the brain harbours smouldering lesions However the smouldering lesions are a product of of peripheral immune activity and this is inhibited

          • Sorry MD, i dont want to harp on with this but i’m struggling a little bit. I understand that the smouldering lesions are a product of the peripheral immune activity. However, CD20 meds also inhibit this, yet are considered to have limited impact on the smouldering disease. Why is HSCT different? yes, it a complete reset but if the disease is still present in the CNS, isn’t nuero-degeneration going to continue?

          • Yes it is going to contiunue and is does so in some individuals. This is why HSCT is recommended for people with active relapsing disease

            The smouldering lesions are a glial cell response within the brain, these could be independent of or conditioned by the lymphocytic response. If they are independent of the peripheral immune response then most MS drugs, including HSCT will probably not affect them. The acts used in HSCT are not targeted at the glial response. If they are conditioned by the immune response then with time the inhibition of the peripheral immune response may have an effect.

            So image the peripheral immune response is a match and when active you get a flame. This them lights a long slow burning fuse (the glial response). You can blow out the match but the fuse still burns and will do so until it gets to the end when the nerve stops working. This process may take 2-3 years to show itself and so it takes a long time to see benefit. For this reason most MS drugs are considered to fail in progressive MS. The trials are too short to show a benefit but they will be beneficial in my opinion. Likewise people feel they are deteriorating on treatment and so may not feel benefit, however compared to no treatment the slope of deteriroation would be slower.

            Now to the MS drugs. We know that the MS drugs target the lesion forming cells. This includes anti-CD20. In the trials there were alot more people with these active lesions to allow benefit to be seen quicker. Blocking the effect of these will show quick benefit and slow deterioration as less fuses are being lit. In Europe anti-CD20 are only prescribable if there is evidence of this activity, but in US they are more liberal meaning people get extra benefit if it works on the CNS lesions or they are paying for more limited efficacy if they dont have active lesions. Most antibody wont get in the CNS, but some will and there it may further stop the fuses burning or help to extinguish them.

            Now to HSCT. This is no different to what I have said above, except that rather than a puff of wind it is a gail and will really blow to extinguish those matches from burning. However the lit fuses will continue to burn. This is why HSCT is recommended for relapsing MS and not progressive/advanced MS as it is most likely to benefit from this treatment. A number of people will not immediately benefit from this because because HSCT is no going to stop those smoldering glial lesions.

            Yes you are correct if

  • MD – i ran out of replies but just wanted to say that i have read A LOT of posts, articles, case studies etc on MS over the last 12 months. This one definitely made the podium. Thank you. Absolute champ

    • Agreed….MD is the best! Pretty sure I would be completely lost (and honestly a bit scared) if it were not for this blog and, in particular, the insights of MD.

      Plus, MD has really done an excellent job filling certain unexpected voids over the past few months. I wish we could nominate him for some type of blog employee of the year award…..

      • The best…..Fiver in the post:-)

        Nominate for prize….steady on their fella..I have not got an award ever…maybe I don’t kiss enough butt?:-).

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