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.)
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.
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.
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.
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.
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
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: firstname.lastname@example.org
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.