This Is MS Multiple Sclerosis Knowledge & Support Community

I think I'm becoming the "Michael Moore" of the pharmaceutical world. HAH! (As a side note, I'm from Flint, Michigan originally, also. Mike Moore graduated a year earlier than I did. He went to a different high school, but I remember him WELL! LOL Flint was not that large, and he used to come in and out of the law firm I used to work at up there years ago, too. Maybe it's just "something in the water" up there. LOL)

Anyway, I digress. Ok...........regarding VLA-4 antagonists. Are they an interesting and potentially highly beneficial find? Absolutely. But, is playing around with VCAM-1 and VLA-4 fairly complex? Absolutely.

Originally, (and HARRY and ROBIN, you're going to find this sort of interesting), our friends at Merck have been looking into VLA-4 antagonists - for quite a while. (Remember our person who migrated from Merck to Biogen? No insinuations there, but can't help but notice the coincidence.) Anyway, we all know that Merck is a fairly gutsy risk taker when it comes to manufacturing pharmaceuticals (i.e. Vioxx). Well, even they slowed down and backed off just a bit on VLA-4 antagonists. That "may" or "may not" say a thing, though. You decide.

Let's play devil's advocate for just a bit, though. I'm going to post a couple of things below that, to me anyway, are of "note" at the very least when making a decision about taking a VLA-4 antagonist.

Ok.....after you read the below........I pose a question to you. IF any of the below is even remotely possible, and IF you were an MS neurologist/immunologist/specialist, and given what we know about MS and pregnancy, etc. etc., what would be YOUR advice to, at the very least, your female MS patients of child-bearing age regarding taking a VLA-4 antagonist for MS? (Remember, at least with the CRABS, you CAN stop taking them if you want to have children, without much of a "rebound" effect.)

Deb



Effects of VLA-4 antagonists in rat whole embryo culture

http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract
Teratology 2002 Jan;65(1):26-37

Spence S, Vetter C, Hagmann WK, Van Riper G, Williams H, Mumford RA, Lanza TJ, Lin LS, Schmidt JA.

Developmental and Reproductive Toxicology, Merck Research Labs, West Point, Pennsylvania 19486.

BACKGROUND:
Pharmacological antagonism of VLA-4 (Very Late Antigen 4, [alpha](4)[beta](1) integrin) has become an attractive target for the treatment of predominantly eosinophil mediated disease states such as asthma, allergic rhinitis, multiple sclerosis, rheumatoid arthritis, diabetes, and inflammatory bowel disease. Gene knockouts of the [alpha](4)-integrin subunit of VLA-4 or its cell surface ligand, VCAM-1, however, have been shown to result in embryo-lethality in homozygous null mice due to defects in chorio-allantoic or epi-myocardial fusion. Although gene knockout phenotypes are not always manifested by pharmacological antagonism, those studies suggested that VLA-4 antagonists might cause embryo-lethality or drug-induced malformations.
METHODS:
To test these concepts, early neurulating rat embryos were cultured by the methods of New ('7 8 ) after intra-coelomic microinjection of a VLA-4 blocking antibody or in the presence of small molecule VLA-4 antagonists.
RESULTS:
Defects in chorio-allantoic fusion were induced after microinjection of VLA4 blocking antibody and after continuous exposure to small molecule antagonists. In a minority of affected embryos chorio-allantoic fusion was completely blocked whereas the majority of affected embryos had only superficial chorio-allantoic fusion and the allantois was enlarged and edematous. Although the allantoic mesoderm covered the trophoblasts of the chorionic plate and contained blood vessels there was only minimal invasion of the trophoblasts by the allantoic mesoderm. The lowest observed effect level generally correlated with the IC([similar]95), as determined in 90% plasma.
DISCUSSION:
Based on these data, VLA-4 antagonism might represent a significant risk to the developing embryo/fetus. In vitro exposure, however, is "constant" and does not take into account the elimination phase of these xenobiotics in vivo. Given the high concentrations required to elicit an effect, therapeutic blood levels in vivo may be several fold lower than those that affect the conceptus, depending on the tissue penetration of the compound and the route of administration. VLA-4 also exists in a range of conformations and activation states in vivo and the gene KOs and present studies do not define whether these developmental processes are dependent upon a particular activation state of VLA-4. Therefore, state-selective antagonists may have an improved embryonic safety profile. Additional studies will be required to determine potential effects of VLA-4 antagonists on embryo/fetal development in vivo.
Copyright 2002 Wiley-Liss, Inc

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Note who also found the following.........just last year. They may have found something further, of course, which will "counteract" this slight possible "catch-22" with a VLA-4 antagonist. We'll just have to wait and see on that one. Please read this next abstract in full, even though I have highlighted a couple of things. At least we do know that BIO 5192 didn't help.

Prepublished online as a Blood First Edition Paper on August 21, 2003; DOI 10.1182/blood-2003-03-0974.

Submitted April 8, 2003
Accepted August 18, 2003

Differential effects of treatment with a small molecule anti-VLA-4 antagonist before and after onset of relapsing EAE

Bradley E Theien, Carol L Vanderlugt, Cheryl Nickerson-Nutter, Mark Cornebise, Daniel M Scott, Stuart J Perper, Eric T Whalley, and Stephen D Miller*
Microbiology-Immunology/Interdepartmental Immunobiology Center, Northwestern University Medical School, Chicago, IL, USA
Biogen Inc., Boston, MA, USA

* Corresponding author; email: s-d-miller@northwestern.edu.

Interaction of VLA-4 with its ligand VCAM-1 is required for CNS migration of encephalitogenic T cells in relapsing experimental autoimmune encephalomyelitis (R-EAE). Anti-VLA-4 mAb treatment prior to EAE onset inhibits disease induction, however, treatment initiated after the appearance of clinical symptoms increases relapse rates, augments Th1 responses, and enhances epitope spreading perhaps due to the activation of costimulatory signals. To negate the potential costimulatory activity of intact anti-VLA-4, we examined the ability of BIO 5192, a small molecule VLA-4 antagonist, to regulate active PLP139-151-induced R-EAE. BIO 5192 administered one week after peptide priming, i.e. before clinical disease onset, delayed the clinical disease onset, but led to severe disease exacerbation upon treatment removal. BIO 5192 treatment initiated during disease remission moderately enhanced clinical disease while mice were on treatment and also resulted in post-treatment exacerbation. Interestingly, BIO 5192 treatment begun at the peak of acute disease accelerated entrance into disease remission and inhibited relapses, but treatment removal again exacerbated disease. Enhanced disease was caused by the release of encephalitogenic cells from the periphery and the rapid accumulation of T cells in the CNS. Collectively, these results further demonstrate the complexity of VLA-4/VCAM interactions, particularly in a relapsing-remitting autoimmune disease.

Oh, yea.............another thing that VLA-4 is VERY integral with is...............

ta da! Stem cells and stem cell migration and mobilization.



Deb

hmmmmmmmmm....this is interesting. It "appears" there may be something of a competitive "race" going on to get a VLA-4 antagonist on the market.

Here's something I ran across on the Encysive Pharmaceuticals website:

"VLA-4 ANTAGONISTS (Pre-Clinical) With a complex biological process such as the one that triggers asthma, there is often more than one way to attack the problem. A case in point is our collaboration with Schering Plough Corporation to discover and optimize VLA-4 antagonist compounds to treat asthma. In June 2002, Schering chose to take one of our VLA-4 antagonists into the final stages of testing prior to beginning clinical development. Unlike other VLA-4 antagonists that are in development, our candidate is a small molecule compound and is therefore orally available. We believe our VLA-4 compound may block the action of certain cell adhesion molecules and thereby prevent inflammation in a highly specific manner."

Here is something out of their May 4, 2004 10-Q:

"We have entered into a worldwide research collaboration and license agreement with Schering-Plough Corporation and Schering-Plough LTD, collectively referred to as Schering-Plough, to discover, develop and commercialize VLA-4 antagonists. Schering-Plough is in the final stages of pre-clinical development with TBC4746, an oral VLA-4 antagonist. If this work is successful, the next development step would be to initiate studies in human volunteers. VLA-4 is a potential target in the inflammatory cascade taking place within the vasculature. TBC4746 has the potential to address a number of diseases, including asthma and multiple sclerosis. Additionally, Schering-Plough has also funded research on a follow-on compound pursuant to the research agreement and such funding will most likely end on June 30, 2004. "

hmmmmmmmmmmm..............something ORAL? Man, I love to research.

Deb

P.S. Please "note" that VLA-4 works via the "vascular" system.....i.e. blood. So.....strokes? Who knows? Maybe...........maybe not.

Here is a good website (I thought) describing integrins: http://www.hosppract.com/issues/2000/03/etzioni.htm

Wow! Here's something interesting: (I can hardly wait to see more clinical results, etc. when they come out. I'm sure something has changed since these research findings came out........)

" J Clin Invest, April 2001, Volume 107, Number 8, 995-1006

Copyright ©2001 by the American Society for Clinical Investigation

--------------------------------------------------------------------------------

Article

Discordant effects of anti–VLA-4 treatment before and after onset of relapsing experimental autoimmune encephalomyelitis

Bradley E. Theien1, Carol L. Vanderlugt1, Todd N. Eagar1, Cheryl Nickerson-Nutter2, Remederios Nazareno3, Vijay K. Kuchroo3 and Stephen D. Miller1

1 Department of Microbiology-Immunology and the Interdepartmental Immunobiology Center, Northwestern University Medical School, Chicago, Illinois, USA
2 Biogen Inc., Cambridge, Massachusetts, USA
3 Center for Neurologic Diseases, Harvard University, Boston, Massachusetts, USA

Address correspondence to: Stephen D. Miller, Department of Microbiology-Immunology, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, Illinois 60611, USA. Phone: (312) 503-7674; Fax: (312) 503-1154; E-mail: s-d-miller@northwestern.edu.

Received for publication November 6, 2000, and accepted in revised form March 13, 2001.

Initial migration of encephalitogenic T cells to the central nervous system (CNS) in relapsing experimental autoimmune encephalomyelitis (R-EAE), an animal model of multiple sclerosis (MS), depends on the interaction of the 4 integrin (VLA-4) expressed on activated T cells with VCAM-1 expressed on activated cerebrovascular endothelial cells. Alternate homing mechanisms may be employed by infiltrating inflammatory cells after disease onset. We thus compared the ability of anti–VLA-4 to regulate proteolipid protein (PLP) 139-151–induced R-EAE when administered either before or after disease onset. Preclinical administration of anti–VLA-4 either to naive recipients of primed encephalitogenic T cells or to mice 1 week after peptide priming, i.e., before clinical disease onset, inhibited the onset and severity of clinical disease. In contrast, Ab treatment either at the peak of acute disease or during remission exacerbated disease relapses and increased the accumulation of CD4+ T cells in the CNS. Most significantly, anti–VLA-4 treatment either before or during ongoing R-EAE enhanced Th1 responses to both the priming peptide and endogenous myelin epitopes released secondary to acute tissue damage. Collectively, these results suggest that treatment with anti–VLA-4 Ab has multiple effects on the immune system and may be problematic in treating established autoimmune diseases such as MS. "

Ok....I'll move on to something else now. Well, in any event, and the goal of this exercise I guess, is that this might be an example of how much you can find out without waiting for media releases. Are integrins (and VLA-4) exciting "works" right now? Yepper!! Sure are! And manipulation of VLA-4, VCAM-1 appears to even be potentially highly BENEFICIAL for stroke, not to mention stem cell research. But it appears to ME anyway that it is still in its infancy. But I've been known to be wrong. I'm not a clinician.

Awwwwwwwwwww..........darn it. It looks like I "fibbed". Here are TWO more abstracts. As one of my sons (he's a hoot) always says "Danger, Will Robinson", I'm going to modify that to "Caution, Will Robinson!" Now I'm done.


Mult Scler. 2004 Oct;10(5):540-8. Related Articles, Links

Macrophage brain infiltration in experimental autoimmune encephalomyelitis is not completely compromised by suppressed T-cell invasion: in vivo magnetic resonance imaging illustration in effective anti-VLA-4 antibody treatment.

Deloire MS, Touil T, Brochet B, Dousset V, Caille JM, Petry KG.

EA 2966 Neurobiology of Myelin Diseases Laboratory, University Victor Segalen Bordeaux 2, Bordeaux, France.

Large inflammatory infiltrates of T cells, macrophages and B cells in the central nervous system (CNS) contribute to the pathogenesis of multiple sclerosis (MS). The passage of T cells through the blood-brain barrier can be suppressed with antibodies directed against alpha-4 integrins (VLA-4) that mediate T-cell adherence. This treatment, in phase III of clinical trial evaluation, reduces lesion development in MS patients. In the ongoing inflammatory disease process the consequences of T-cell inhibitory anti-VLA-4 antibodies on inflammatory compounds are still poorly investigated. We show that anti-VLA-4 antibody treatment during the late preclinical phase of the acute experimental autoimmune encephalomyelitis (EAE) MS rat model interrupts T-cell egress out of the vascular compartment and suppresses clinical disease and histological alterations but macrophage recruitment in the CNS is not fully compromised. Among the treated EAE animals not developing disease, none presented foci of T-cell infiltration in CNS. However, in 75% of the treated EAE rats monocyte ingress in CNS was observed in vivo by magnetic resonance imaging with the ultrasmall superparamagnetic iron oxide contrast agent. Our data shed new light on the role of remaining macrophage brain infiltration in an induced but interrupted T-cell-mediated EAE disease process.

PMID: 15471371 [PubMed - in process]
****************************************

Proc Natl Acad Sci U S A. 2004 Jul 27;101(30):11058-63. Epub 2004 Jul 19. Related Articles, Links


VLA-4 integrin concentrates at the peripheral supramolecular activation complex of the immune synapse and drives T helper 1 responses.

Mittelbrunn M, Molina A, Escribese MM, Yanez-Mo M, Escudero E, Ursa A, Tejedor R, Mampaso F, Sanchez-Madrid F.

Servicio de Inmunologia, Hospital de la Princesa, Universidad Autonoma de Madrid, Madrid 28006, Spain.

The integrin alpha 4 beta 1 (VLA-4) not only mediates the adhesion and transendothelial migration of leukocytes, but also provides costimulatory signals that contribute to the activation of T lymphocytes. However, the behavior of alpha 4 beta 1 during the formation of the immune synapse is currently unknown. Here, we show that alpha 4 beta 1 is recruited to both human and murine antigen-dependent immune synapses, when the antigen-presenting cell is a B lymphocyte or a dendritic cell, colocalizing with LFA-1 at the peripheral supramolecular activation complex. However, when conjugates are formed in the presence of anti-alpha 4 antibodies, VLA-4 colocalizes with the CD3-zeta chain at the center of the synapse. In addition, antibody engagement of alpha 4 integrin promotes polarization toward a T helper 1 (Th1) response in human in vitro models of CD4(+) T cell differentiation and naive T cell priming by dendritic cells. The in vivo administration of anti-alpha 4 integrin antibodies also induces an immune deviation to Th1 response that dampens a Th2-driven autoimmune nephritis in Brown Norway rats. These data reveal a regulatory role of alpha 4 integrins on T lymphocyte-antigen presenting cell cognate immune interactions.

PMID: 15263094 [PubMed - indexed for MEDLINE]

JUST A NOTE:

THIS THREAD IS A SPIN-OFF FROM ANOTHER DISCUSSION STARTED ON THE THREAD ENTITLED "Biogen Idec".

http://www.thisisms.com/modules.php?nam ... opic&t=560

YOU MAY ALSO BE INTERESTED IN VIEWING THAT THREAD, ALSO.

THANKS.

OddDuck wrote:These data reveal a regulatory role of alpha 4 integrins on T lymphocyte-antigen presenting cell cognate immune interactions.

So is that a good thing for Brown (or any other flavour) Norway rats, or me?

Sorry to be a bio-dummy I'm very much learnign this new way of speaking!

Yea, that's the thing. And that statement is just a general one. Actually, it's a good thing for the rats for THAT disease, but could be a bad thing for MS in many ways.

The thing is, a VLA-4 antagonist stops T-cell migration, but does NOT stop macrophage migration into the brain and/or CNS. For some conditions, that can be a good thing, but in MS, that is NOT always a good thing.

So.....basically, a VLA-4 antagonist can stop the immune system T-cells from entering the brain, but will not stop APCs from entering the brain. So, the probability is that IF any types of MS pathogenesis is from antigens sneaking in and isn't solely an immune system dysfunction, then in the long run, that is a bad thing. (Hence, that may be where and why we are hearing the rumors about Antegren not working for long. Even the findings from Biogen that I posted above indicate the same thing.)

The thing with a VLA-4 antagonist, though, is that when it is used in connection with stem cell research, the very fact that it is so potent and does manipulate what crosses the blood-brain barrier and blocks "certain" other things from crossing COULD be helpful. If you want stem cells to cross over the BBB without interruption from other bodily processes trying to stop them, then it could be great. (Again, though, all this research is in its infancy and a VLA-4 antagonist is nothing to just play around with.)

The other possible problem, though, is the fact that it doesn't allow ANY T-cells to cross. Hence why it says that over time, the body switches to a mainly TH1 immune response. In MS, you want to keep your immune system predominantly TH2. Plus, this allows a HUGE margin for infection, etc. to run rampant should you ever pick something up.

My question also then is...........you DO want the "good" interleukines to do its work in MS (i.e. such as IL10, and other anti-inflammatory cytokines), so if you take Antegren as a monotherapy, how long WILL it take before it stops working? And especially since Antegren only works via ONE mechanism of action, where are the balancing mechanisms that you need to balance out what it's doing?

I think the advice that person got (that I posted above - no wait, maybe it was in another thread - but I won't name names) from her neuro was a good one. Antegren MAY need to be used in combination with something else.

Biogen's OWN research points out many possible difficulties, doesn't it? That's what I found a little disturbing, shall we say. What changed in under a year with their research? Or is getting Antegren on the market more for the goal of supplementing stem cell research in the future?

It's going to get interesting, I'd say.

Deb

Oh.....actually........here's the bottom line of it all, that Biogen ITSELF found:

"...Collectively, these results suggest that treatment with anti–VLA-4 Ab has multiple effects on the immune system and may be problematic in treating established autoimmune diseases such as MS. "

I just couldn't find ANYWHERE, from any researchers, that VLA-4 antagonists had yet been "manipulated" or combined with anything to any extent where the above statement may now prove to be false.

That's why I say it'll be interesting to see what research Biogen has been holding back. Actually, I don't think it's research at all. I personally think that the only thing Biogen has been holding back is clinical trial results on humans. Which "might" mean nothing much as far as whether all of the above laboratory findings by them (and many others) has changed at all!

I would just use extreme caution and be VERY prudent before proceeding with Antegren. That's all. Just exercise extreme caution. (Of course, that's just MY personal advice. Take it or leave it.) Maybe I'd suggest that a person pose these very same probing questions to their neuro first, before proceeding with Antegren, also. It never hurts.

Deb

Ok...here's a bit of an explanation regarding myelin degradation in MS. I forgot to mention that a VLA-4 antagonist does not stop B cells from crossing, either. It only stops T cells. So....if some types of MS ARE exacerbated due to B cells, that could pose a problem, also. The following is just an excerpt that helps describe some of the complex problems that happen in MS:

"....This chaos of chemicals causes the inflammation of the blood-brain barrier, thinning it so that T-cells, B-cells and macrophages may enter. Macrophages complete the process by stripping the myelin sheath directly off the nerves. In turn, they release necrosis factor alpha, which is believed to damage oligodendracytes - the cells that produce myelin - making the damage irreparable. (2) The replication of T-cells, the secretion of more and more cytokines, and the eventual destruction caused by the macrophages is cyclic. The myelin can be come inflamed, swollen, or even detached from the nerve fibers. Eventually, it is destroyed and hardened patches of scar tissue form over the fibers (5)."

In any event, another bottom line that I state is that it is important to maintain a "balance" of physiological processes when treating MS.

Oh, and did you know that interferon-1b (Betaseron) has some effect on VLA-4 also, but isn't as potent and does have some other mechanisms of action that balance things out. (And as another plug for my pet project, desipramine also helps strengthen the BBB by minor action on VLA-4.) So..........IFN1b does much of the same thing. Well, there's a positive for a CRAB, huh? I believe you DO want to strengthen the BBB in MS, but just how much? Ya know? I don't think that's the sole answer, is all.

I hope this helps.

Deb

Well, as always, I keep following up on myself.

As a new thought, you know under what circumstances that I think Antegren MAY prove to be more useful? In stopping inflammation during an extreme inflammatory MS exacerbation. Right then. Instead of using a steriod.

And remember, all of this only applies to RRMS, not for progressive MS.

But.........for use as an "ongoing" constant therapy? Man....I'm sorry, but I have my extreme doubts.

I hope I'm proven wrong.

Deb

Ya know..............I alluded earlier in this thread about the connection between VLA-4 and people of child-bearing age (".... studies suggested that VLA-4 antagonists might cause embryo-lethality or drug-induced malformations.")

For some reason, I got back on that thought again this morning, and I did a bunch more research. I won't post it all, but if you all know me by now, you know I've GOT it!

Anyway, the bottom line is that integrins (including VLA-4) are VERY integral in female AND male fertility, and in connection with miscarriage, too. If you inhibit VLA-4 (especially via a potent VLA-4 antagonist) there is substantial research to indicate that may grossly interfere with fertility, conception (VLA-4 is necessary in order for implantation in the womb to take place), and miscarriage (the lack of activation of VLA-4, for one, has been shown to be connected with miscarriage).

You know what the problem with all this is that bothers me? HAS anyone done full investigative research into how a VLA-4 antagonist does or might affect fertility, etc? In BOTH men and women.

I mean, for us oldie-moldies, that wouldn't be much of a concern. But since there is nothing really that indicates that you should NOT consider having a family when you have MS (plenty of MSers have had children, and/or decided to start families), what about the younger generation just starting out? Although it's better probably to stop taking the CRABS for a while during pregnancy, and I haven't run across anything at all that says the CRABS affect male fertility at all, what about messing with VLA-4 in people of child-bearing (and rearing) ages?

I don't know about anyone else, but I'm going to watch CLOSELY for the contra-indications or side-effects of Antegren. I want to see if they find what I found, and if they warn the public of the "potential" hazzards of this. OR see if any research with regard to interfering with integrins and the results on fertility and reproduction by doing so starts being published.

Deb

EDIT: And you know what? Before starting all this research, I really didn't have that much of an opinion on whether a VLA-4 antagonist such as Antegren was going to be helpful or not. I use caution with everything anyway, but until this week's research exercise, I didn't have a real strong opinion either way about Antegren. Man........I hate to say it, but NOW I do! Shoot!

Deb: what an interesting point you raise... one that may be worth pursuing with Biogen/Elan given its serious implications. One has to hope that the best and brightest at these organizations would have considered the negative effects of this treatment approach, but then again, just look at Vioxx...

I know......unfortunately, the Vioxx situation has brought so many things under an extra "microsope" now, huh?

And truly, I never expected to find something like that, either. I hope I don't sound like I'm trying to predict doom and gloom or am using any kind of "scare" tactic at all. I tried to just stick with the facts as I ran across them.

But frankly, I feel similar to how you just phrased it. I'm "uncomfortable" about it..........but hopeful that something just hasn't been brought to light yet that will reassure me (and everyone else) about this issue.

Deb

Thanks Deb for your posts here - glad I asked the question now.

Caution I agree has to be the watchword in our desire (hope) for some definite treatment.

I'm interested that you too draw a distinction bewteen RR and SP/PP. I can see how from a consideration of symptoms (espcially if one is in the progressive camp) you might make the distinction but when considering any specific treatment how can one say, "It doesnt work for SP/PP!" Ok so we might postulate that there are two critical points where sufficient CNS damge has been done that a move from RR=>SP (do people move RR=>PP ?) and from SP=>PP are triggered (and that would have enormous variabilty across also sorts of factors), but my understading - and I'm probably way out, misinformed and exposing my bio-ignorance - is that ones internal CNS condition, at least as shown by an MRI, does not correlate with apparant symptoms. So if that's the case why deny SP/PP folk any treatment judged efficaious for RR? Surely that can only be said after a long term study!

EDIT:: Am I saying here that the amount of caution one applies to any given drug is qualified by comparing ones current quality of life with the possible gain - back to risk assessment!

2nd EDIT:: Picked this up from your post on the another thread Deb

remember, not all MSers experience inflammation - i.e. progressive MS

- I've not found that point made anywhere, or more likely just "read" over it. Every day I just realise there is so much more to learn!