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Depleting B cells in the CNS With Rituximab

Discussion in 'Other Health News and Research' started by Ecoclimber, Sep 7, 2014.

  1. Ecoclimber

    Ecoclimber Senior Member

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    Permission to repost courtesy of Prof. G:

    Depleting B cells in the CNS

    Studer V, Rossi S, Motta C, Buttari F, Centonze D. Peripheral B cell depletion and central proinflammatory cytokine reduction following repeated intrathecal administration of rituximab in progressive Multiple Sclerosis. J Neuroimmunol. 2014 Aug 19. pii: S0165-5728(14)00850-9. doi: 10.1016/j.jneuroim.2014.08.617. [Epub ahead of print

    B cells and/or the enhanced inflammatory milieu in the subarachnoid space are supposed to have a role in cortical pathology of progressive multiple sclerosis (PMS). The efficacy of intravenous rituximab to deplete circulating B cells is remarkable in MS, and its intrathecal delivery could target compartmentalized inflammation in PMS.

    We describe the central and peripheral effects of repeated intrathecal rituximab administrations in a patient with severe PMS. Peripheral CD20+ B cells were reduced, while oligoclonal bands were unaffected. Several central proinflammatory cytokines, and markers of neurodegeneration were markedly reduced.


    [​IMG]

    The agents that affect relapsing MS all can target B cells within the peripheral (Blood) compartment. But many of these agents will not penetrate into the CNS. Some people think that progressive MS may be a problem within the central (CNS) compartment (area). So one way to look at this is to deliver B cell depleting agents into the CNS. This can be come by intrathecal delivery. In this study antibody was delivered in to the central compartment and enough got into the blood to deplete the peripheral compartment. Anti-CD20 depletes many B cells but not the B cells producing antibody (plasma cells) and so maybe you would not think that oligoclonal bands (antibodies within spinal fluid) would be depleted. But some markers of inflammation were reduced.

    However is spinal deliver of antibodies a viable treatment? Well if it works one can make a case however it says why not get a drug that can deplete B cells in the peripheral and central compartments. There are already drugs that could do this, why not give them a go...Oh they are outside their patent life so pharma won't development them.
    This is also probably the fate for rituximab.Should neuros do trials with drugs that they may not be able to get pharma to develop?

    This is a debate that needs to be debated and solutions found

    8 comments:




      • [​IMG]
        Matt PerrySaturday, September 06, 2014 9:34:00 am
        Which drugs are you referring to (that deplete B cells in CNS and peripheral)?
        Thanks!

        MouseDoctorSaturday, September 06, 2014 10:08:00 am
        There a few anti-cancer drugs but none approved for ms yet
        Saturday, September 06, 2014 10:20:00 am
        Disappointing that oligoclonal bands were unaffected. Does that suggest intrathecal rituximab will be no more helpful than intravenous for progressive MSers?


        Also: Does the paper say anything about the MSer's progression after treatment?
        Intravenous rituximab slowed progression in younger patients with enhancing lesions.

        IngridSaturday, September 06, 2014 10:44:00 am

        Prof G, how would you rank Rituximab with regard to efficacy compared to Fingolimod, Alemtuzumab and Natalizumab? I know there is no Rituximab-trial but would you put it into the "highly effective class"? Closer to Fingolimod or closer to Natalizumab?

        I tried to find something about sideeffects. Seems to me it is generally well tolerated. I could not find anything which seems as serious as the autoimmunity-issues from Alemtuzumab or PML from Natalizumab. Did I miss anything?

        Alemtuzumab is recommended to be used as early as possible. Would you consider it for someone failing Fingolimod?

        Any idea when Ocrelizumab might become available?

        Saturday, September 06, 2014 12:55:00 pm
        You need anti-CD19 treatments to target plasmablasts. That should, theoretically, seriously benefit the health of PPMSers, perhaps even SPMSers.

        But no-one is genuinely pushing this strategy. Progressive MS, which really is what all MSers have at varying degrees, is the true area that needs effective remyelination treatments. That is the only way to properly treat MS. This blog need to convey more reporting on this area.

        MouseDoctorSaturday, September 06, 2014 1:36:00 pm
        your info is incorrect there are anti cd19 studies on going.
        More info on this study will surface in due course

        Saturday, September 06, 2014 6:56:00 pm
        "Should neuros do trials with drugs that they may not be able to get pharma to develop?" Yes, if there is clinical need and pharma does not want to spend the $. Academic medicine needs to be more proactive in areas that are deemed "less profitable" by drug companies.

        MouseDoctorSaturday, September 06, 2014 10:27:00 pm
        I agree but the question is how is this done?

        Whilst it may seems like a daft question but in recent times the history of neuros achievements without pharma input is......em
     
    Last edited: Sep 7, 2014
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  2. alex3619

    alex3619 Senior Member

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    Logan, Queensland, Australia
    Sigh, we faced this ourselves with trying to get Rituximab trials running. Patents are expiring. However I wonder if this is valid for biologicals? While the competitors can create analogs, they will not be the same drug. So expiry of patents might not matter as much.
     
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  3. Ecoclimber

    Ecoclimber Senior Member

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    My understanding is that NIH Collins initiated a program for drug repurposing and rescue of off patent drugs. One such example.

    A repurposing approach identifies off-patent drugs with fungicidal cryptococcal activity, a common structural chemotype, and pharmacological properties relevant to the treatment of cryptococcosis.
    Butts A1, DiDone L, Koselny K, Baxter BK, Chabrier-Rosello Y, Wellington M, Krysan DJ.
    Author information
    • 1Department of Chemistry, University of Rochester, Rochester, New York, USA.
    Abstract
    New, more accessible therapies for cryptococcosis represent an unmet clinical need of global importance. We took a repurposing approach to identify previously developed drugs with fungicidal activity toward Cryptococcus neoformans, using a high-throughput screening assay designed to detect drugs that directly kill fungi.

    From a set of 1,120 off-patent medications and bioactive molecules, we identified 31 drugs/molecules with fungicidal activity, including 15 drugs for which direct antifungal activity had not previously been reported.

    A significant portion of the drugs are orally bioavailable and cross the blood-brain barrier, features key to the development of a widely applicable anticryptococcal agent. Structural analysis of this set revealed a common chemotype consisting of a hydrophobic moiety linked to a basic amine, features that are common to drugs that cross the blood-brain barrier and access the phagolysosome, two important niches of C. neoformans.

    Consistent with their fungicidal activity, the set contains eight drugs that are either additive or synergistic in combination with fluconazole. Importantly, we identified two drugs, amiodarone and thioridazine, with activity against intraphagocytic C. neoformans.

    Finally, the set of drugs is also enriched for molecules that inhibit calmodulin, and we have confirmed that seven drugs directly bind C. neoformans calmodulin, providing a molecular target that may contribute to the mechanism of antifungal activity.

    Taken together, these studies provide a foundation for the optimization of the antifungal properties of a set of pharmacologically attractive scaffolds for the development of novel anticryptococcal therapies.


     
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