Why do I think using antibodies are a dubious way to treat brain disease

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Repulsive guidance molecule A (RGMa) is upregulated following injury to the central nervous system (CNS), where it is believed to induce neuronal destruction and inhibit axonal growth and remyelination (It is also involved in bone development). Elezanumab, is an anti-RGMa monoclonal antibody that blocks RGMa, This study is a early trial in humans and suggests one thing to me and this is why I pick it out for discussion.

Kalluri HV, Rosebraugh MR, Misko TP, Ziemann A, Liu W, Cree BAC. Phase 1 Evaluation of Elezanumab (anti-RGMa mAb) in Healthy and MS Participants. Ann Neurol. 2022 doi: 10.1002/ana.26503. PMID: 36093738.

Objective: To describe the safety, tolerability, pharmacokinetics, and immunogenicity of elezanumab (ABT-555), a fully human monoclonal antibody (mAb) directed against Repulsive Guidance Molecule A (RGMa), in healthy and multiple sclerosis (MS) study participants.

Methods: The single-center, first-in-human, single ascending dose (SAD) study evaluated elezanumab (50mg-1600mg IV and 150mg SC) in 47 healthy men and women. The multi-center multiple ascending dose (MAD; NCT02601885) study evaluated elezanumab (150mg, 600mg, and 1800mg) in 20 adult men and women with MS, receiving either maintenance or no immunomodulatory treatment.

Results: No pattern of study drug-related adverse events were identified for either the SAD or MAD elezanumab regimens. Across both studies, the time to maximum drug concentration occurred within 4 hours of elezanumab IV infusion, and the time taken for half the drug to disappear ranged between 18.6-67.7 days (this often about a month for many antibodies). Following multiple dosings, elezanumab maximum concentration increased dose-proportionally and resulted in dose-dependent increases in elezanumab CSF concentrations (So the more antibody you give the more antibody gets into the brain). Elezanumab CSF penetration was 0.1-0.4% across both studies (so only a 500th to a thousandth of what you inject gets into the brain so it means that 99.6% -99.9% of what you inject with the view of targetting the brain is wasted. As such they have to inject massive amounts of antibody in this case about 12-133 times the amount of alemtuzumab injected in a day or about up to 27 times the amount of alemtuzumab used for the year or 3 times the dose of ocrelizumab that would be used in 6 months, but this would last 2 weeks so about 18 times the dose equivalent of ocrelizumab or over 20 times the monthly dose of natalizumab and this is only enough to deplete the target by 40%) with CSF levels of free RGMa decreased by over 40%. Changes in CSF free RGMa demonstrated dose/exposure-dependence. (The more you give the more gets into the brain)

Interpretation: The elezanumab pharmacokinetic profile supports monthly, or bi-monthly, administration of up to 1800mg with the option of a loading dose of 3600mg (How many hours is this going to take?). Elezanumab partitioning into CSF is within the range expected for mAbs. (So here is my point. The level of antibody getting into the CNS is rubbish….with 99.9% going down the proverbial toilet) Reduced CSF levels of free RGMa levels demonstrate central nervous system target binding of elezanumab with an apparent maximal effect at 1800mg IV.

So in terms of treating brain disease with a antibody that really doesn’t get in the brain seems a bit of a mad-idea to me.

What do I know? A scientific ameoba against the science brains of pharma and their academic advisors.

However, I’m not spending hundreds of millions on a drug development pathway lasting years that is going to kill off a useful target….including many people careers. It is clear that antibodies can treat brain disease. However for ocrelizumab, rituximab and alemtuzumab one has to ask. “Is the action of the antibody in the blood.?” But here they have been used to target events occurring in the brain.

We have seen this approach being tried over and over again. Such as with remyelinating antibody in MS, in an approach that has now been binned as the trial data wasn’t good enough. Then with Alzheimers inhibiting antibodies that have been binned as the trial data wasn’t good enough or the academic community thought that the results were not that good. Then we had the anti-viral antibodies that have so far failed in MS and now we have this early study reported (Above). However, guess what?…We have heard the top-line results of the trials in MS and you can guess what happens.

RADIUS-R (NCT03737851) and RADIUS-P (NCT03737812), two randomized double-blind, placebo-controlled studies evaluating the safety and efficacy of elezanumab in combination with standard of care therapy in patients with relapsing (RADIUS-R) and progressive (RADIUS-P) forms of MS over one year. The primary endpoint was the overall response score (ORS), derived from three performance assessments evaluating changes in disability. Results showed no difference between elezanumab and placebo in both studies, suggesting that this drug does not help to restore neurological deficits in MS.…I don’t feel like a rocket scientist but sometimes I wonder….What’s the next antibody concept to be binned?

We have the DoDo (Double Dose) study thought up by ProfG, where they are using a mega dose of ocrelizumab to get more into the brain as small people benefit more than heavy people….but is this a sensible way to go?….or Do you simple dose people according to their size and ask do you see comparable effects on progression? Too late….The study is ongoing. Time will tell.

Yep these types of posts do me know favours as they seem critical of my peers, but surely you need that little boy to talk about the Emperor’s New Clothes,

CoI: None relevant

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MouseDoctor

17 comments

  • We all know this from FAILED clinical trials/drugs used to treat brain cancer and the failed RTX studies administered intrathecally for MS. This failed concept of poor BBB penetration by MAbs, now replicated in ANOTHER study, is old wine in new bottles. Why do we need new studies to explain a decidedly OLD concept that we are all aware of ?

    1. There is progress in the development of anti-cancer therapeutics, including molecularly-targeted agents, and novel immunotherapies. Both of these modalities are clearly efficacious towards tumors at the primary site, however, it remains a struggle to deliver these therapeutics across an intact BBB to many metastatic sites in the brain (excerpt from Pharm Res. 2018 Jul 12; 35(9): 177). Drugs to treat primary brain cancers are not getting across the BBB, either.

    2. Rituximab is a chimeric monoclonal antibody that targets CD20, which is exclusively expressed on pre‐B and mature B cells, but not on plasma cells. Clinical trials of intravenous rituximab have demonstrated reductions in MRI and clinical activity in RRMS patients, who, as a group, have opened blood–brain barrier (BBB) in the CNS areas with concentrated inflammation (as measured by CELs on brain MRI). However, rituximab had no efficacy on clinical outcomes in PPMS, who lack CELs, strongly supporting the notion that deficient penetration of the therapeutic antibody to affected CNS tissue may underlie lack of its efficacy (excerpt from Ann Clin Transl Neurol. 2016 Mar; 3(3): 166–179).

    There are obviously countless studies that allude to this well-worn concept. I am not sure we are adding anything new. Salami science does not really advance science.

    • how about bi-specifics to get antibodies into brain? One arm to target something the other arm to get the antibody through the brain

  • At least with an anti-CD20 we know it affects blood outside the CNS and if there’s decent homeostasis, B-cells will get shoved back across the blood-brain-barrier to make up for their sudden disappearance in the rest of the body (and get them out of the cerebro-spinal fluid, to be destroyed peripherally by the anti-CD20).

    I managed to get myself off Ocrevus and switched over to Mavenclad and part of my reasoning was it’s small enough to cross the blood-brain-barrier and get into any B & T cells on the brain-side… fingers crossed that is the case and it works.

    In general unless antibodies are being injected directly into the cerebro spinal fluid (and I ain’t volunteering for that trial!) then as you say, they’re just gonna float around in the blood till they’re expelled. It’s not a good way to get into the brain.

      • I think those studies were fundamentally flawed because they used tiny amounts of rituximab and they were done instead of a regular peripheral dose rather than in addition to one. Surely it is obvious that you still have to deplete the periphery even if you find a better way to get drugs into the brain? And surely it is obvious that if peripheral concentrations of the antibody aren’t high, the stuff you inject into the brain will just pour out of the brain and into the periphery? Let’s see someone do 600 mg rituximab IV plus 50 mg rituximab intrathecal. If that fails it will convince me the approach is wrong.

        • It is flawed Maybe

          When injeted into the spine the antibody was washed straight out into the blodd to deplete the B cells in the blood. It was done more than once.

          Why would you target CD20 to get rid of antibody producing cells that dont express CD20″

          How would do this? Not pharma as it is not approved for MS, maybe the Swedes

          We have done this with cladribine study ongoing..

          Maybe will be done with CART therapy and this will give the answer

      • but you said it could be it was injected in the lower stream instead of the upper stream of CNS.

        Or the antibody doesn’t have the “pressure” to go into tissues and they just flow out and may catch just a few targets on their way out where they need to be circulating.

      • Trying to send a suggestion-

        Small trial to treat intractable Lupus using anti CD19 CAR T cells worked.

        https://doi.org/10.1038/s41591-022-02017-5

        B cells began to return after 100 days and were not reactive when they returned. Other articles referring to this paper discuss B cell diseases including MS. The CD19 target hits plasma cells while CD20 target does not- one reason for better results. Also that they aren’t permanently B cell depleted. Something to consider for MS? Someone should do a CD19 Car T cell trial.

        • Absolutely facinating…I heard about plans to do in MS this about 3-4 years ago and I thought yes but is it safe enough….Depleting B cells for cancer to stop a life threatening is on thing but in MS, I was concerned that the construct had no safety signal to stop the car-Ts after they have done their job as no B cells forever would have consequences but to see the results its amazing I have to digest it and cant read it on lap topasfigures too small. I need to work out if the returning B cells are selected for CD19 negativity and what I have to eat some cake, especially after this post

  • Asking, not questioning….: what about the potential “deep tissue” aspect of some antibody therapies? And is it known whether cladribine penetrates the aforementioned “deep tissue” better than larger molecule mabs perhaps? And when I say “deep tissue”, what the heck am I talking about…epithelial cells?

  • I was in the phase 2a clinical trial of Elezanumab. It turns out I was on the placebo. I actually did have sustained improvement while in the trial. EDSS from a 6 to a 3. My MS Specialist joked with me that I probably skewed the results.
    However, my question is that though it may be unlikely that an antibody makes a difference in the brain, what about spinal cord lesions. This drug is proceeding in SPI trials. I think they were using the wrong application of the drug in MS. It is an unfounded theory, but I wonder if SPI does respond to this drug, why not use it in MS patients suffering a relapse with spinal cord lesions?

    • Thank you for your insight and your participation in the study and if it work for you that is fantastic, clearly there is supportive biology and maybe in some people there can be entry into the CNS. Maybe with a bit of blood brain barrier you get more in and good point about the spinal cord as it is a lot smaller and so if the antibody gets in the distance needed to travel may be less compared to the brain.

      I looked on the website and trials are ongoing in spinal cord injuries and acute ischemic stroke. This is a better place to start studies because there is a process to deal with, but in MS this process is recurring and unless you stop the cause happening you may be fighting a lossing battle. Maybe the MS trial you had to be on a highly active disease modifying drug

      • Thank you for the response. Yes you are correct, I did continue on my DMT throughout the trial, so I reasoned my progress within the trial must have been due to my slow, but continuing recovery from my relapse at the end of 2018.

  • I was in the phase 2a clinical trial of Elezanumab. It turns out I was on the placebo. I actually did have sustained improvement while in the trial. EDSS from a 6 to a 3. My MS Specialist joked with me that I probably skewed the results.
    However, my question is that though it may be unlikely that an antibody makes a difference in the brain, what about spinal cord lesions. This drug is proceeding in SPI trials. I think they were using the wrong application of the drug in MS. It is an unfounded theory, but I wonder if SPI does take respond to this drug, why not use it in MS patients suffering a relapse with spinal cord lesions?

  • I was in the phase 2a clinical trial of Elezanumab. It turns out, I was on the placebo. I actually did have sustained, measurable improvement in the trial, while continuing also on my DMT. EDSS went from 6 down to a 3. My MS Specialist later joked with me that I probably skewed the results.
    However, my question is that though it may be unlikely that an antibody makes a difference in brain lesions, what about spinal cord lesions? This drug is proceeding in SPI (spinal cord injury) trials. I think that they were studying the wrong application of the drug in MS. I wonder, if SPI does respond to this drug, what if it were applied after a relapse involving spinal cord lesions. Currently there is nothing they can do to slow down or stop a relapse involving spinal cord lesions. (My specialist has told me steroids are not used for spinal cord lesions because they are not effective for them.)

    • You make an excllent point about when the drug is applied and it is most likely to work best when used after recent damage for example it is easier to remyelinate a recently demyelinated lesion than a chronically demyelinated lesion.

      Sorry for slow response and lauch of post every post has to be approved before it becomes vidible

      • Thanks so much for reply. (Sorry for accidentally posting the same response several times. )
        Yes, it seems more difficult to repair set in lesions, but I think more needs to be applied to stop lesion growth while they are forming.

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