Uyttenhove C, Gaignage M, Donckers D, Nasr Z, Cheou P, van Snick J, D'Auria L, van Pesch V. Prophylactic treatment against GM-CSF, but not IL-17, abolishes relapses in a chronic murine model of multiple sclerosis. Eur J Immunol. 2018. doi: 10.1002/eji.201847580. [Epub ahead of print]
The pathogenic role of IL-17 and GM-CSF has been unravelled in experimental autoimmune encephalomyelitis (EAE), a murine (mouse or rat) model of multiple sclerosis (MS). However, in most models (Meaning C57BL/6 mice, Lewis rat and marmoset) , EAE is characterised by a monophasic attack which is not representative of the relapsing nature nor the chronicity displayed in MS. Here, we used proteolipid protein peptide (PLP139-151 ) to trigger EAE-relapses (EAE-II) in SJL mice that had recovered from a primary-EAE episode (EAE-I). This procedure resulted in severe and irreversible disease that, unlike EAE-I, was not abolished by anti-IL-17-mAb (In virtually all papers published anti-IL17 ameliroates but does not abolish disease) . In contrast, prophylactic anti-GM-CSF-mAb treatment prevented EAE-I and -II. Strikingly, the expression of T-cell transcription factors and cytokines/chemokines in mice treated with anti-GM-CSF during both EAE episodes was silenced. Anti-GM-CSF-mAb treatment administered only during EAE-II did not completely prevent relapses (Therefore it will probably fail in MS) but mice ultimately reached full recovery. (I doubt it, we can always see residual deficits if you look) Anti-GM-CSF treatment also strongly impaired and ultimately resolved monophasic MOG35-55 -induced EAE in C57Bl/6 mice. In such protected mice, anti-GM-CSF treatment also prevented a further relapse induced by MOG-revaccination. These results underscore the critical role of GM-CSF on pro-inflammatory mediator production. Furthermore, we observed a strong preventive and curative effect of anti-GM-CSF neutralisation in two EAE models, relapsing and chronic. Altogether these findings are relevant for further MS research. (How?)
So where are we on this one?
Anti-IL17 failed (no better than interferon beta) in MS, anti-IL-12/23 failed in MS, anti-IL-12 failed in relapsing EAE, but not in the monophasic model and if you believe this work the same for IL-17 too. Therefore, it would say animal models say don't do anti-IL17 or anti-IL23/12, but the neuros did it anyway and failed. This is because science dogma has won over common sense.
Most neuros up to now would say rubbish EAE, because it didn't predict the failure in MS. However for the IL-12/23 the EAE study was done before failure and was ignored. However it does suggest the over-reliance of EAE from C57BL/6 models doesn't help.
Pharma like to see data from at least two or more models before they take the plunge, but academics have their blinkers on and in my opinion do many rubbist phase II studies destined to fail. (Good to get that off my chest, but not what you want to hear, I'm sure).
Are neuros going to say let's do an anti-GMCSF trial as the EAE data supports it. But hey, why wait for the right EAE experiment. They're off again.
Randomized phase 1b trial of MOR103, a human antibody to GM-CSF, in multiple sclerosis.
Constantinescu CS1,
Asher A1,
Fryze W1,
Kozubski W1,
Wagner F1,
Aram J1,
Tanasescu R1,
Korolkiewicz RP1,
Dirnberger-Hertweck M1,
Steidl S1,
Libretto SE1,
Sprenger T1,
Radue EW1.
OBJECTIVES: To determine the safety, pharmacokinetics (PK), and immunogenicity of the recombinant human monoclonal antibody MOR103 to granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with multiple sclerosis (MS) with clinical or MRI activity.
METHODS: In this 20-week, randomized, double-blind, placebo-controlled phase 1b dose-escalation trial (registration number
NCT01517282), adults with relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS) received an IV infusion of placebo (n = 6) or MOR103 0.5 (n = 8), 1.0 (n = 8), or 2.0 (n = 9) mg/kg every 2 weeks for 10 weeks. Patients had to have ≤10 gadolinium (Gd)-enhancing brain lesions on T1-weighted MRI at baseline. The primary objective was safety.
RESULTS: Most treatment-emergent adverse events (TEAEs) were mild to moderate in severity. The most frequent was nasopharyngitis. Between-group differences in TEAE numbers were small. There were no TEAE-related trial discontinuations, infusion-related reactions, or deaths. Nine patients experienced MS exacerbations: 3, 5, 1, and 0 patient(s) in the placebo, 0.5, 1.0, and 2.0 mg/kg groups, respectively. A few T1 Gd-enhancing lesions and/or new or enlarging T2 lesions indicative of inflammation were observed in all treatment groups. No clinically significant changes were observed in other clinical assessments or laboratory safety assessments. No anti-MOR103 antibodies were detected. PK evaluations indicated dose linearity with low/no drug accumulation over time.
CONCLUSIONS:MOR103 was generally well-tolerated in patients with RRMS or SPMS. No evidence of immunogenicity was found.
Although it seems safe, there is no hint of efficacy
After this event we have
Emily R. Pierson and Joan M. Goverman GM-CSF is not essential for experimental autoimmune encephalomyelitis but promotes brain-targeted disease. JCI Insight. 2017; 2(7): e92362.
Duncker PC, Stoolman JS, Huber AK, Segal BM.GM-CSF Promotes Chronic Disability in Experimental Autoimmune Encephalomyelitis by Altering the Composition of Central Nervous System-Infiltrating Cells, but Is Dispensable for Disease Induction.
J Immunol. 2018; 200:966-973
What Comes first Chicken or the Egg?
It seems clinical trial then EAE data to fit the results of the trial. This is hardly predictive use of animals. We then do loads of experiments trying to understand why the trial failed, but in reality the approach of doing this will have limited value because a new trial is unlikely to be repeated. OK it is knowledge creation, but animmals will suffer in the name of this science.
However that makes the assumption that neuros have learned from the past, to not plough on. But maybe we will be glad for this behaviour.
It happens, as Ibudilast (Chemical anti-TNF) seems to do something in progressive MS, when it failed in relapsing MS just as rolipram (Chemical anti-TNF with same target mechanism) and anti-TNF (antibodies and fusion proteins) had done before.