Do central nervous system anti-CD20 effects matter?

D

Barts-MS rose-tinted-odometer: ★★★ (gray Friday; overcast and miserable #3a3b3c)

It was not easy writing this blog post; I hope it makes sense. I was asked the other day ‘what defines a low versus a high-dose B-cell depleting anti-CD20 therapy?’.

Unlike with small molecules the dose of monoclonal antibodies is not necessarily about drug/antibody levels, but how much of the target gets inhibited or depleted and then how long these effects last. So when I compare ocrelizumab (600mg intravenously every 6 months) with ofatumumab (20mg subcutaneously every month) is there a difference? Yes and no; it depends on whether or not you take into account the potential CNS effects of these agents.

No in the sense that both of these doses are likely to keep circulating peripheral B-cell numbers very low and seem to have similar effects when it comes to suppression of inflammatory MS activity, i.e. relapses, focal MRI lesions, relapse associated-worsening and possibly even a component of PIRA (progression independent of relapses). 

It is clear that ocrelizumab is a higher dose and is having a greater effect on deep tissue B-cells. The half-life of circulating monoclonal antibodies is partially determined by the circulating concentration vs. the quenching effect of the target antigen. The more circulating antibody around, the longer its half-life. The more target antigen around, i.e. CD20+ B-cells, the lower half-life of the antibody because the antigen binds to and removes antibody from the circulation. Following B-cell depletion, the half-life at steady state for ofatumumab is estimated to be approximately 16 days (FDA ofatumumab prescribing information) compared to  26 days for ocrelizumab (FDA ocrelizumab prescribing information). 

Other differences supporting the low vs. high dose differences relate to B-cell repopulation kinetics. For ofatumumab B-cell counts reach the lower limit of normal in at least 50% of patients in 24 to 36 weeks after stopping treatment, which equates to a median time to B-cell recovery of ~40 weeks post-treatment discontinuation (FDA ofatumumab prescribing information). For ocrelizumab, the median time for B-cell counts to return to either baseline or the lower limit of normal is 72 weeks (range 27-175 weeks) (FDA ocrelizumab prescribing information).

Based on the above there is little doubt that ocrelizumab is higher-dose than ofatumumab. Is this relevant? I think it may be if part of the mode of action of B-cell depletion therapies is to target B-cells and B-cell follicle-like structures within the CNS of pwMS.  The amount of antibody that crosses the blood-brain barrier is roughly 0.5% of what is circulating in the periphery; as steady-state levels are higher with ocrelizumab more of it is likely to cross the blood-brain barrier and affect CNS and meningeal B-cells.

We are only one of many groups that hypothesise that the intrathecal or CNS B-cells, plasma cells and antibodies (oligoclonal bands) are pathogenic in MS and are driving some of the smouldering pathologies we see in MS. This is why we are exploring therapies such as proteasome inhibitors (ixazomib), cladribine, BTK inhibitors and high-dose ocrelizumab to see if we can scrub the CNS clean of OCBs. So yes, based on this hypothesis I think the dose of ofatumumab may be too low to affect intrathecal B-cells. A clue to this is that there was no dose effect, based on body size, on disability progression noted with ofatumumab compared to that seen with ocrelizumab. Why?

Dose-response relationships in biology are often S-shaped. I suspect the intrathecal effects of ofatumumab based on body size is on the flat part of the S-curve. In comparison with the higher body-size based doses of ocrelizumab, the intrathecal/smouldering MS effects are on the linear part of the curve and hence why there is a clear signal (see dosing imaging below). There is a way to investigate this hypothesis involves doing detailed CSF studies comparing what happens within the spinal fluid of patients on ocrelizumab high-dose vs. ocrelizumab standard-dose vs. ofatumumab standard-dose. I hypothesize there will be a clear ladder on the impact on CNS B-cell biology. At the same time, we can ask what is the impact of this anti-CD20 dosing tier is on meningeal B-cell follicle-like structures, slowly expanding lesions, subpial cortical lesions, brain volume loss, CSF NFL levels, etc.?

So yes, I do think ofatumumab is a low-dose anti-CD20 therapy and ocrelizumab is a higher-dose anti-CD20 therapy. This explains why I helped push/nudged Roche-Genentech to design and run their own version of our proposed DoDo (double-dose) ocrelizumab study. The good news is that these high-dose ocrelizumab trials are recruiting rapidly and we should have an answer to some of these questions in the next 3-4 years.

Based on the above I am also against low-dose rituximab dosing in MS. I think we need high-dose CNS-penetrant anti-CD20 therapies; at least initially. Once you have purged the CNS of B-cells and B-cell follicle like structures the dose can probably be reduced. 

Please, let me know if this post makes sense? Thanks.  

Slide from Hauser et al. AAN 2019.

CoI: Please note I sit on the steering committee of Roche-Genentech’s high-dose ocrelizumab programme. 

Conflicts of Interest

Preventive Neurology

Twitter

LinkedIn

Medium

General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice. 

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

44 comments

  • How can this be? You have been telling us that monoclonal antibodies don’t cross the blood-brain barrier and don’t get into the brain.

    • Not me. I did my PhD in a CSF laboratory and was taught that the CSF levels of antibodies are ~1/200th their levels in the blood. If they don’t get in how do you explain the effect of aducanumab in clearing amyloid from the brains of people with Alzheimer’s disease. When we look for OCBs using iso-electric focusing we run the CSF neat in parallel with serum diluted 1 in 200; this ratio is chosen for a reason.

      MONOCLONAL ANTIBODIES DO CROSS THE BLOOD-BRAIN BARRIER!

    • I don’t know because the correct dose was never found in a proper phase 2 or 3 trials. I suspect anything lower than about 2g every 6 months is a low dose. What we need are studies looking at the impact on CSF biomarkers of B-cell and plasma cell biology are required.

  • Would it make sense to find a way to deliver these drugs directly to the “other side” of the blood-brain barrier? Or is the answer, “only if you want to kill people, don’t mess with the blood-brain barrier”?

      • Would it make sense to find a way to deliver these drugs directly to the “other side” of the blood-brain barrier?

        That has allready ben done …And no effect 🙁

        Insufficient disease inhibition by intrathecal rituximab in
        progressive multiple sclerosis

        While CSF B cells were killed robustly (median
        79.71%, P = 0.0176), B cells in CNS tissue were depleted inadequately
        (~10–20%, P < 0.0001). Consequently, the T-cell-specific CSF biomarker
        sCD27 decreased slightly (10.97%, P = 0.0005), while axonal damage marker,
        neurofilament light chain did not change. Insufficient saturation of CD20, lack
        of lytic complement, and paucity of cytotoxic CD56dim NK cells contribute to
        decreased efficacy of rituximab in the CNS

        https://pubmed.ncbi.nlm.nih.gov/27042677/

        • The problem with intrathecal rituximab administration into the lumbar sac is that it is a CSF outflow pathway and hence the drug doesn’t get into the tissues of the brain and spinal cord; it simply gets flushed out into the periphery.

          • Ok
            Lets try a diferent route them

            “via a ventricular catheter inserted into the right frontal horn and connected to a subcutaneous Ommaya reservoir”

            No effect again 🙁

            Intrathecal treatment trial of rituximab in progressive MS: An open-label phase 1b study

            https://pubmed.ncbi.nlm.nih.gov/30305449/

            Of 7 clinical assessments, only 1 showed statistically significant improvement 1 year after treatment. No treatment effect was observed during the follow-up period among 6 CSF biomarkers.

  • Thanks Prof G. Some difficult issues to understand for a non-scientist.

    “We are only one of many groups that hypothesise that the intrathecal or CNS B-cells, plasma cells and antibodies (oligoclonal bands) are pathogenic in MS and are driving some of the smouldering pathologies we see in MS.”

    My Mickey Mouse questions are:

    – Does the CNS of a healthy person (non-MSer) contain intrathecal or CNS B-cells, plasma cells and antibodies, or are they there because of MS?
    – If it is possible to scrub the CNS clean of OCBs, what does this mean for the patient eg stopping smouldering MS, halting progression, allowing some remyelination of SELs? Won’t the OCBs just return after treatment has finished?
    – With your betting hat on, what approach is likely to be more successful – double dosing of existing anti-CD20 therapies, or the new kids on the block (proteasome inhibitors (ixazomib), cladribine, BTK inhibitors)?

    • Hi Sid
      The CNS of a healthy person is essentially free of B cells, plasma cells and antibodies except at very low level, I would suggest 0.1% of plasma levels, you’ll find the odd lonely T cell mooching around.
      If we’re right about the pathogenicity of OCBs and their potential to activate microglia then removing them could put out the smouldering underlying MS. No reason the OCBs should return if B cell entry to the CNS is stopped.
      I reckon the anti-CD20s won’t be effective as CD20 isn’t on plasma cells leaving the new kids on the block as the most promising approaches.

      • Thanks.

        It’s good to see so many trials planned or underway to test the various hypotheses relating to progressive MS / smouldering MS, particularly those relating to CNS B-cells, plasma cells…

      • Do plasma cells express CD52? Is there any chance this could be one reason for the greater efficacy of alemtuzumab on brain atrophy rates?

        • Yes, plasma cells do express CD52. Alemtuzumab can reduce CSF OCBs but not eliminate them completely suggestive of incomplete penetrance into the CNS.

    • ” Does the CNS of a healthy person (non-MSer) contain intrathecal or CNS B-cells, plasma cells and antibodies, or are they there because of MS?”

      Pender says healthy people can have them in CNS but they die from apoptosis..but EBV gives
      b cells anti-apoptotic molecules that allows them to survive in the CNS.

  • Yes, for me, the pwMS, this makes perfect sense and is written in a way I can perfectly understand. Btw, reading your blogs I have learned so much about MS (tho, it is quite sad I haven’t learned not even 1 % about MS from my neuro, thus thank you for writing), and I think knowing as much as I can about MS is of crucial importance for living with MS – so big thank you!

  • Is there anything that exists or being trialed to helps the antibodies cross the BBB, such as a lipids that can get access to the CNS that trick the BBB to allow certain molecules in.

    I’m sure I’ve read this somewhere.

    • Yes, there are so-called nanobodies that cross the BBB quite well; these are made from camel antibodies.

      • There are antibodies with attached parts of protein that are actively transported in the CNS but no one is beyond phase I trial and maximum concentration is not higher than 5% of blood

  • Hi Prof G – do you have any theories on whether switching to ofatumumab is beneficial vs not for patients who have been on ocrelizumab for a long time (4+ years)? Could ofatumumab be a maintenance option after higher doses of ocrelizumab, or would you be more concerned that b-cells deeper in the body would start coming back on the ofatumumab?

  • Is it still possible to participate in the high dosis Ocrelizumab studies if I am living in Germany? Any further information about this?

      • Thank you, I will look into it. Maybe this is my way to get into an Ocrelizumab treatment, my neurologist is hesitant to put me on it since my course of disease is too “benign”. I am 32, M, dx in 2012, since then on rebif, and had until now at least two quite severe relapses affecting my spine, the last one was in winter 2019 and did not recover fully with an impact on my gait and other things. Sorry for the text, I am a bit frustrated, since my mum (in her 60ies now) has also MS and I know what can happen without proper treatment…

        Keep the great work on this blog and stay safe and vaccinated 🙂

        • “at least two quite severe relapses affecting my spine, the last one was in winter 2019 and did not recover fully with an impact on my gait and other things.”

          This is very far from benign ms…get away from that neuro
          now before you really suffer damage. Benign ms doesn’t exist but if it did it would be one relapse every 3 or 4 years..and 100% recovery from them. Since you haven’t had ms long you’d probably get more recovery possibly 100% if you did hsct now.

      • Dear Mousedoctor,
        I am having an appointment for a first talk regarding a participation in that study. Do you have suggestions what I should ask them? I am a bit scared of starting Ocrelizumab (on whatever dose) just a few months before the next Corona variant (delta) hits us. I have got two shots of the Moderna vaccine though. It is also a bit scary to get three times the standard dose (1800mg every 24 weeks instead of the usual 600mg)…
        Thank you for your work in the lab and on this blog.

        Best regards

  • This is really interesting and useful to know. Still, in the world of covid, I am leaning towards ofatumumab on the basis of potential vaccine boosters readiness.

    • The risks of MS are infinitely greater than the risks of COVID, especially if you are otherwise young and healthy… I don’t think you should let COVID vaccination influence your choice of MS treatment at all.

      • Good point, though my Covid concerns come from the fact that I’ve tended to have MS episodes after major illnesses. So my Covid concerns are actually MS concerns.

  • Unfortunatly Abbvie elezanumab drug ( repair drug ) has failed to meet their primary endpoint and will not pursue it further in Spms and Rrms.

  • Regarding high dose B-cell depletes and their ability to penetrate the CNS and effect B-cell follicular tissue in the meninges; haven’t we learned from intrathecal rituximab studies that the abs do not penetrate these follicular structures enough to impact pathology inside the CNS?

    The BTKi inhibitors may have more efficacy on these structures and scrubbing the CNS free of B cells. Does this make sense?

    • >haven’t we learned from intrathecal rituximab studies that the abs do not penetrate these follicular structures enough to impact pathology inside the CNS?

      The problem with the intrathecal rituximab studies is that they didn’t actually succeed in what they set out to do. The rituximab flowed right back out into the periphery, so it just acted like a normal rituximab infusion.

  • Why hypothesize about anti-CD20 dosing, when there is already an existing DMT, which is the only small molecule drug currently available and is a proven to penetrate the CNS and eliminate all memory B-Cells…..Cladribine 😉

  • Well if it’s one disease…then all it takes to stop ppms in it’s tracks…is
    high dose anti-cd20….Somehow this seems too good to be true…

    But if it’s not shouldn’t someone be testing this on compassionate care basis trial.
    Oops sorry I forgot no-one…is willing to risk anything…easier to stand by as people whither.

  • Prof G,

    “We are only one of many groups that hypothesise that the intrathecal or CNS B-cells, plasma cells and antibodies (oligoclonal bands) are pathogenic in MS and are driving some of the smouldering pathologies we see in MS.”

    How widespread among MS research teams is support for the hypothesis? If it is widespread, why are Team G running all the trials to test the hypothesis (or are other teams running other trials)?

    I often read research papers which refer to “compartmentalised inflammation in the brain”. Is this the same thing as the smouldering MS hypothesis?

    • Why we are runnign trials because we are ahead of the curve

      No I think this refers to lesions in Brain eg meningeal infiltrates it has nothing to do with smoldering MS in the heads of the people talking about compentatized

  • Re:
    If they don’t get in how do you explain the effect of aducanumab in clearing amyloid from the brains of people with Alzheimer’s disease.
    This finally convinced me, there it was on screen to see as clear as day. I need to re imagine my picture of the BBB to be more like a barricade that can be broken through by a crowd!
    Re:
    I am also against low-dose rituximab dosing in MS
    Not sure rituximab is being prescribed anywhere where a licensed anti CD20 is available and affordable? But is used as an alternative to less effective treatments (eg in Sweden) or in countries when few or no licensed treatments available. Maybe for rituximab need to compare apples with oranges.

    Ps re:
    gray Friday; overcast and miserable #3a3b3c
    Loving the colour palette themed posts, eventually gave up and Googled the # 🙂

    • Anti-lingo 99.9% excluded 0.1% gets in..feeling generous 1% gets in. You have to give 100mg of antibody……..As effect of aducanumab 3 people have already resigned for the FDA Neurology committee in response to the approval

      • “As effect of aducanumab 3 people have already resigned for the FDA Neurology committee in response to the approval”

        This decision is only loved on wall street..? Make money now if it doesn’t
        work it will literally take years to determine this…seen some patients
        swear by it though…people are desperate for anything now even if it doesn’t work.

        • Yes, but nobody says it is not getting into the CNS and clearing amyloid. The latter is the point I am trying to make. You need relatively high-doses of monoclonal antibodies if you want to target intrathecal of CNS pathology.

      • Morning MD
        There did appear to be a lot of unknowns re effectiveness of aducanumab in treating Alzheimers… but no doubt about it getting into the brain!

        So, for MS, mega dose of monoclonals or time to go back to traditional small molecule chemistry?

        Ixazomib trial so-ooo exciting!

By Prof G

Translate

Categories

Recent Posts

Recent Comments

Archives