Interessenkonflikte. A Lutterotti has received honoraria and travel support from Bayer Schering Pharma, Biogen Idec, Merck Serono and Novartis.

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1 Interessenkonflikte A Lutterotti has received honoraria and travel support from Bayer Schering Pharma, Biogen Idec, Merck Serono and Novartis.! A is listed as coinventor on a University Hospital Zürich patent for the use of anfgen- coupled cells in MS.

2 Neue Therapieansätze bei MS - aktuelle Strategien am Universitätsspital Zürich Andreas Lutterotti Universität Zürich

3 Neuroimmunologie und MS Forschung Entwicklung neuer Therapiestrategien bei MS Frühe Phase Studien (I-IIb)! Prä-klinische Sicherheit! Regulatorische Aspekte! Studien design Pathogenese Biomarker! Untersuchung von Wirk- und Krankheitsmechanismen! Entwicklung von Biomarkern! Klinische Forschung! Entwicklung neuer Outcome Parameter! Studien designs! Stratifizierung Mitarbeiter im klinischen Studienteam! Magdalena Foege Tamara Eng Claudia Blumer Andre Winkler

4 AKADEMISCHE THERAPIEFORSCHUNG Grundlagen! Forschung Akademische Therapieforschung & Entwicklung Pharma Industrie Identifikation von Krankheitsprozessen Wahl von geeigneten Patienten Wahl von geeigneten Studiendesigns/Parametern Entwicklung von neuen Strategien auf Basis von Erfahrung in Patientenbetreuung Brückenschlag zwischen Klinischer Forschung und Industrie

5 IMMUNMODULATORISCHE THERAPIEN BEI MS Annualized relapse rate -32% -54% -68% Placebo IFN-ß / GA Fingolimod Natalizumab Die Effektivität in der Reduktion von entzündlicher Krankheitsaktivität ist zuletzt immer besser geworden, aber mit einem hohen Risiko für schwerwiegende Nebenwirkungen verbunden. Wiederauftreten der Kranlheitsaktivität nach Beendigung hoch effektiver Therapien Wenig Fortschritt gab es in therapeutischen Ansätzen zur Neuroprotektion, Remyelinisierung, Regeneration etc.

6 UNERREICHTE THERAPIEZIELE BEI MS Immuntherapien mit hoher Effektivität und geringem Risiko. Entwicklung von Therapien, die die autoimmune Grundlage der Erkrankung direkt beeinflussen. Neuroprotektion. Remyelinisierung. Regeneration. Verbesserung von belastenden Symptomen (Fatigue, Kognition ua.).

7 UNERREICHTE THERAPIEZIELE BEI MS Immuntherapien mit hoher Effektivität und geringem Risiko. Entwicklung von Therapien, die die autoimmune Grundlage der Erkrankung direkt beeinflussen. Neuroprotektion. Remyelinisierung. Regeneration. Verbesserung von belastenden Symptomen (Fatigue, Kognition ua.).

8 RNS60! Physikalisch modifizierte Kochsalzlösung Hergestellt durch Anreicherung von Sauerstoff unter Taylor- Couette-Poiseuille Fluss.! Chemisch besteht RNS60 aus 0.9% Kochsalzlösung und Sauerstoff (NaCl, H2O, O2).! RNS60 enthält keinen pharmazeutischen Bestandteil.

9 Biotechnology and Applied Biochemistry (2009) 53, ( ) Durch die Herstellung unter Rotation und spezifischer hochenergetischer Flussdynamik entstehen Nanostrukturen um einen Sauerstoffkern mit spezifischer Ladung (sog. Nanobläschen).

10 their respective quadrants. B) The mean fluorescence intensity (MFI) of IL-4 in CD4+ population was calculated by using CellQuest software. C) Supernatants Figure 6. Regulation were assayed of Th2 for cellsil-10 by RNS60, by ELISA. NS, Data PNS60, areand mean RNS SD of LNC three isolated different from MBP-immunized experiments. a donor p,0.001 EAE+RNS60 micevswere control; (300 stimulated ml/mouse/d) b p,0.001 with vs MBP. D) LNC 2/5 0.8 isolated MBP in the from presence MBP-immunized of 10% v/v ofdonor RNS60, mice NS, PNS60, wereor stimulated RNS10.3. A) with After MBP 72 hinofthe stimulation, presence T cells or absence were incubated of RNS60 with appropriately diluted PEconjugated anti-cd4 and FITC-conjugated anti-il-4 Abs followed by FACS analysis. The percentage of relevant cells EAE+NS (10% is indicated (300 v/v) in ml/mouse/d) and NS (10% v/v), respectively their respective 5/5 3.5 followed by FACS analysis with appropriately diluted PE-conjugated anti-gata3 and FITC-conjugated anti-cd4 Abs. The percentage of relevant cells is their indicated respective in their quadrants. respective B) The quadrants. mean fluorescence E) The MFI intensity of GATA3 (MFI) in of CD4+ IL-4 in population CD4+ population was calculated was calculated by using CellQuest software. C) Supernatants were assayed for IL-10 by ELISA. Data are mean 6 SD of three different experiments. a by using CellQuest p,0.001 vs control; b software. Data are mean 6 SD Effekt von p,0.001 vs MBP. D) LNC of isolated three from different MBP-immunized experiments. donor a RNS60 p,0.001 mice were vs stimulated control; b im Tiermodell EAE was induced der in female Multiplen SJL/J mice through adoptive Sklerose transfer of MBP-primed T cells. From 0 dpt, mic p,0.001 with MBP vs in MBP. the presence F) LNC or isolated absence from of RNS60 MBP-immunized (10% v/v) and donor NS (10% mice v/v), were respectively stimulated with MBP in injection (dpt 1 8, alternate day; dpt 9 16, daily; dpt 17 onwards, alternate day). While a clinical score of the followed presence by FACS or analysis absence with of appropriately RNS60 or NS, diluted for 48PE-conjugated h followed anti-gata3 by monitoring and FITC-conjugated the mrna expression anti-cd4 Abs. of IL-10 The percentage and GATA3ofby relevant semi-quantitative cells RT-PCR. score of 0 was considered to be normal. Results is indicated represent in their respective three independent quadrants. E) experiments. The MFI of GATA3 in CD4+ population was calculated by using CellQuest software. Data are mean 6 SD doi: /journal.pone g006 of three different experiments. a p,0.001 vs control; b a p,0.001, p,0.001 vs MBP. F) LNC isolated from MBP-immunized donor mice were stimulated with MBP in the presence or absence of RNS60 or NS, for 48 h followed by monitoring the mrna expression of IL-10 and GATA3 b p,0.01 by semi-quantitative vs EAE (control). RT-PCR. Results represent three independent experiments. doi: /journal.pone t001 doi: /journal.pone g006 cytometric analysis of splenocytes for Foxp3 (Tregs), IL-17 & RORct (Th17), IFN-c & T-bet (Th1), and IL-4 & GATA3 (Th2). prophylaktische Gabe cytometric Asanalysis expected, of splenocytes induction of foreae Foxp3 markedly (Tregs), therapeutische decreased IL-17 & CD4+Foxp3+ Gabe RORct (Th17), Tregs IFN-c (Fig. 11A), & T-bet increased (Th1), andthe IL-4 levels & GATA3 of CD4+IL-17+ (Th2). (Fig. 11B) As expected, andinduction CD4+RORct+ of EAE markedly (Fig. 11C) decreased Th17 cells, CD4+Foxp3+ upregulated the levels of Tregs (Fig. CD4+IFN-c+ 11A), increased (Fig. the11d) levels and of CD4+IL-17+ CD4+T-bet+ (Fig. (Fig. 11B) 11E) Th1 cells, immune system and CD4+RORct+ (Fig. 11C) Th17 cells, upregulated the levels of and down-regulated CD4+IL-4+ (Fig. 11F) and CD4+GATA3+ cells including CD4+IFN-c+ (Fig. 11D) and CD4+T-bet+ (Fig. 11E) Th1 cells, and down-regulated (Fig. 11G) CD4+IL-4+ Th2 cells. (Fig. However, 11F) andtreatment CD4+GATA3+ of EAE mice with (Fig. 11G) RNS60, Th2 cells. but not However, NS, led treatment to the protection of EAE mice of CD4+Foxp3+ with Tregs RNS60, but (Fig. not 11A), NS, led to suppression the protectionofof CD4+Foxp3+ CD4+IL-17+ Tregs (Fig. 11B) and (Fig. 11A), CD4+RORct+ suppression (Fig. of CD4+IL C) Th17 cells, (Fig. decrease 11B) andin CD4+IFN-c+ CD4+RORct+ (Fig. 11D) (Fig. and 11C) CD4+T-bet+ Th17 cells, decrease (Fig. 11E) in CD4+IFN-c+ Th1 cells, and increase in (Fig. 11D) CD4+IL-4+ and CD4+T-bet+ (Fig. (Fig. 11F) 11E) andth1 CD4+GATA3+ cells, and increase (Fig. in11g) Th2 cells, CD4+IL-4+ compared (Fig. 11F) to and untreated CD4+GATA3+ EAE mice. (Fig. 11G) Th2 cells, compared to untreated EAE mice. Figure 7. Effect of RNS60 on clinical symptoms of adoptivelytransferred relapsing-remitting EAE in mice and encephalitogenicity of MBP-primed T cells. A) EAE was induced in female SJL/J mice by adoptive transfer of MBP-primed T cells. From 0 dpt, mice were RNS60 suppresses RNS60 suppresses EAE in mice EAE viaintregs mice via Tregs Next, in Next, order to intest order the to functional test thesignificance functional ofsignificance RNS60- of RNS60- mediated mediated increase inincrease Treg activity, in Treg we examined activity, we whether examined RNS60whether RNS60 protected protected mice frommice clinical from symptoms clinical ofsymptoms EAE via Tregs. of EAE At first, via Tregs. At first, we checked we whether checkedrns60-induced whether RNS60-induced MBP-primed Tregs MBP-primed were Tregs were capable of capable suppressing of suppressing the adoptivethe transfer adoptive of EAE transfer in female of EAE in female SJL/J mice. A single injection of RNS60-induced Tregs on 4 dpt SJL/J mice. A single injection of RNS60-induced Tregs on 4 dpt markedly suppressed the clinical symptoms of EAE in recipient mice in acute markedly as wellsuppressed as relapsing phases the clinical of the disease symptoms (Fig. of 12A). EAE in recipient This result mice wasinspecific, acute as aswell CD4+CD252 as relapsing non-tregs phases of remained the disease (Fig. 12A). unable tothis inhibit result the disease was specific, process ofas RR-EAE CD4+CD252 (Fig. 12A). These non-tregs remained results suggest unable RNS60-induced to inhibit thetregs disease areprocess capableof ofrr-eae suppressing (Fig. 12A). These EAE. results suggest RNS60-induced Tregs are capable of suppressing Next, we EAE. examined whether RNS60 treatment also protected EAE via Tregs. Next, Therefore, we examined during RNS60 whether treatment, RNS60 the treatment function also protected of Tregs was blocked in vivo in EAE mice by anti-cd25 antibody. EAE via Tregs. Therefore, during RNS60 treatment, the function As evident from Figure 12B, RNS60 treatment ameliorated clinical symptoms of Tregsof was RR-EAE. blocked However, in vivo in functional EAE mice blocking by anti-cd25 antibody. CD25 antibody As evident almost completely from Figure abrogated 12B, the RNS60 RNS60-mediated protective clinical effect symptoms on EAEofmice RR-EAE. (Fig. 12B). However, This result functional was blocking anti- treatment ameliorated specific as CD25 control antibody IgG hadalmost no suchcompletely effect (Fig. abrogated 12B). Together, RNS60-mediated protective delineate aneffect important on EAE role of mice Tregs (Fig. in RNS60-12B). This result was these results mediatedspecific protection asof control EAE. IgG had no such effect (Fig. 12B). Together, these results delineate an important role of Tregs in RNS60- Discussion mediated protection of EAE. MS is an autoimmune disease resulting from activation and proliferation Discussion of myelin-reactive T cells that cross the blood-brain barrier to enter the CNS. Once there, these cells initiate, promote, and aggravate MSmultifaceted is an autoimmune inflammatory Figure disease and8. degenerative resulting RNS60 insults inhibits from activation the progression and of adoptively- Mondal et al. PLOS ONE 2013 surface or secre generally conside with Treg prop homeostasis [1,2 Tregs could be a T cells in MS. It has been sh number of CD4 + Foxp3 in relapsi autoimmune di Foxp3+ Tregs m autoimmune Th disorders. Accor mechanisms that study. Although immunomodulat agent to achieve saline to Taylo presence of ele (Tacoma, WA) h active pharmace RNS60 is propo consisting of an electrical double have been sugge drug delivery [3 biological effects Here we dem due to TCP turb conclusion is ba reported earlier, T cells. However MBP-primed T saline preparatio RNS10.3 (TCP

11 Immunomodulation by RNS60 Immunomodulation by RNS60 Figure 10. RNS60 inhibits demyelination in the CNS of EAE mice. Cerebellar (A) and spinal cord (B) sections of control EAE (16 dpt), and either RNS602 or NS-treated EAE mice (16 dpt receiving RNS60/NS from 8 dpt) were stained with Luxol fast blue. Digital images were collected under bright field setting using a 406 objective. (C) Demyelination was represented quantitatively by using a scale as described in materials and methods. Data are expressed as the mean 6 SEM of five different mice. PLOS ONE 7 December 2012 Volume 7 Issue 12 e51869 Prophylaktische Gabe von RNS60 hemmt a p,0.001 vs control; die Entzündung b p,0.001 vs EAE. Cerebellum of control, EAE and either zentralen RNS602 or NS-treated EAE mice was analyzed for MBP and CNPase by semi-quantitative RT-PCR (D) and quantitative real-time PCR (E). Data are expressed as the mean 6 SEM of five different mice. a p,0.001 vs control; b p,0.001 vs EAE. doi: /journal.pone g010 Nervensystem von during Mäusen Helminth infection bymit suppressing EAE. the development of Th1 that of RNS60-treated MBP-primed T cells induced the clinical response. Similarly, Kohm et al [21] have shown that supplementation of Tregs by adoptive transfer before active and adoptive treatment of EAE animals with RNS60 was also capable of symptoms of EAE in naïve female SJL/J mice. Therapeutic Therapeutische Gabe EAE inductionvon significantly RNS60 reduces the severitywirkt of clinical disease, sich inhibiting bei themäusen invasion of mononuclear mit cells into EAE cerebellumpositiv and auf das potentially by promoting a disease protective Th2 immune spinal cord, as well as the expression of inflammatory molecules response. Here we also must remember that Tregs produce (inos and IL-1b), and restored myelination and the expression of Fortschreiten der substantial Erkrankung. amount of IL-10, a cytokine that is also produced by myelin genes within the CNS. In order to directly prove the Th2 cells. Therefore, whether the stimulation of Th2 response by involvement of Tregs, we transferred RNS60-induced Tregs to RNS60 is a direct inhibits effect of therns60, production an of indirect NO and effect the via expression EAEofmice inosand, a different experiment, used an anti-cd25 RNS60 hemmt die enrichment Entzündung of Tregs, MBP-primed or both, needslnc further und and study. splenocytes Abbau and that antibody avon NO donor in RNS60-treated Myelinscheiden EAE mice. Suppression of EAE in by Mäusen mit Because Tregs have abrogates been implicated RNS60-mediated in the pathogenesis restoration and/or of upregulation RNS60-induced of Tregs and abrogation of RNS60-mediated cells. Finally, Tregs are autoimmune also known diseases, Foxp3 we examined suggest the thateffect RNS60 of RNS60 boosts treatment Tregs via suppression protection of of NOEAE by anti-cd25 antibody clearly suggest that EAE. on the disease process production. of RR-EAE. Here we delineate the first RNS60-induced Tregs are capable of ameliorating EAE and that evidence that TCP-modified The major salinefunction RNS60ofinhibits Tregs thetodisease maintain immune the effect homeostasis. Adoptively-transferred While Tregs suppress MBP-primed the proliferation T cellsof autoimmune Tysabri and Th1different forms of interferon-c (IFN-c) are currently of RNS60 treatment is Treg-dependent. process of RR-EAE. RNS60 erhöht die remained Zahl unablevon to induce cells byregulatorischen clinical secretingsymptoms TGF-b and of IL-10, EAE intregs female release IL-35 used Entzündungszellen. to totreat control MS. However, reduced effectiveness and severe toxic Figure 9. RNS60 inhibits infiltration of mononuclear cells and inflammation in the CNS of EAE mice. Cerebellar (A) and spinal cord (B) sections of control EAE (16 dpt), and either RNS602 or NS-treated EAE mice (16 dpt receiving RNS60/NS from 8 dpt) were stained with H & E. Digital images were collected under bright field setting using a 406objective. Infiltration (C) and cuffed vessel (D) were represented quantitatively by using a scale as described in materials and methods. Data are expressed as the mean 6 SEM of five different mice. a p,0.001 vs control; b p,0.001 vs EAE. Cerebellum of control, EAE and either RNS602 or NS-treated EAE mice was analyzed for inos and IL-1b by semi-quantitative RT-PCR (E) and quantitative real-time PCR (F). Data are expressed as the mean 6 SEM of five different mice. a p,0.001 vs control; b p,0.001 vs EAE. doi: /journal.pone g009 any effect on CD4. The unperturbed expression of CD4 probably implies that either suppression of Foxp3 by MBP-priming or upregulation of Foxp3 by RNS60 treatment is not due to any reduction of CD4 + suppressor T cells as they suppress immune responses of other cells. Accordingly, suppression of IFN-c expression in MOGprimed tomato red T cells by RNS60-induced Tregs suggests that RNS60-induced Tregs are functionally active. Mechanisms by which Tregs could be restored SJL/Jduring mice receiving an the RNS60. proliferation In contrast, of autoimmune MBP-primed Th17 T cells cells effects [1,4,34,37,38]. over chronic use, as well as treatment costs, often limit these autoimmune insult are poorly understood. Recently, inducedwe EAE have in miceaccordingly, receiving NS. wefrom founda therapeutic that RNS60point suppresses of available both Th1therapies. and For example, IFN-c has a number of side delineated that NO is a critical regulator of Foxp3view, and Tregs it is important [17]. toth17 test whether immunea drug responses. candidate Theoretically, is efficacious Tregs effects should including also flu-like symptoms, menstrual disorders in women, PLOS ONE 2013

12 Rationale für den erstmaligen Einsatz von RNS60 bei MS Ein positiver biologischer Effekt wurde in Modellen (Labor, Tierversuch) gezeigt. Das Nebenwirkungsprofil ist vermutlich gering. In einem ersten Versuch in gesunden Probanden sind keine wesentlichen Nebenwirkungen aufgetreten

13 Studiendesigns Kontrollierte Studie (randomisiert/nicht-randomisiert) Gruppe 1 Gruppe 2 Gruppe 3 Experimentelle Therapie - Dosis A Experimentelle Therapie - Dosis B Placebo / Vergleichstherapie Gruppe 1 Gruppe 2 Exp. Therapie Placebo Placebo Exp. Therapie

14 Studiendesigns Gruppe keine Therapie Experimentelle Therapie Vergleich -Vor vs Nach Therapie Vorteile des Studiendesigns Geringe Patientenzahl Kein Placebo MRT guter Sicherheitsparameter

15 Clinical Study Protocol! Treatment of Relapsing-Remitting Multiple Sclerosis with RNS60 Administered Intravenously! Open-label, baseline-to-treatment, two-center, phase IIa trial. EUDRA-Ct number: ! Ziel der Studie:! Die Effektivität, Sicherheit und Verträglichkeit von intravenöser Gabe von RNS60 bei Patienten mit schubhafter MS Zielparameter:! Vergleich der Anzahl von kontrastmittelaufnehmenden Läsionen im MRT des Gehirns vor Therapie (8 Wochen) und nach Therapie (Woche 8-16) Einschluskriterien:! Patienten mit schubhafter MS (EDSS 0-0.5) Krankheitsdauer! 5 Jahre >2 KM-aufnehmende Läsionen in den 3 MRTs vor Therapiebeginn Medikation:! RNS ml über 30 Minuten (iv), wöchentliche Infusion für 16 Wochen, zweiwöchentlich Woche 16-24, vierwöchentlic Woche n=16 RRMS Patienten

16 WICHTIGE UNERREICHTE THERAPIEZIELE BEI MS Immuntherapien mit hoher Effektivität und geringem Risiko. Entwicklung von Therapien, die die autoimmune Grundlage der Erkrankung direkt beeinflussen. Neuroprotektion. Remyelinisierung. Regeneration. Verbesserung von belastenden Symptomen (Fatigue, Kognition ua.).

17 A tolerant approach Despite a long record of failure, a few immunologists continue to pursue precisely targeted therapies for autoimmune diseases. BY KEN GARBER 418 NATURE VOL MARCH 2014

18 Voraussetzung für eine Tolerisierungsstudie Verständnis über: Immunologische Krankheitsmechanismen der MS Relevante Zielstrukturen (Antigene) der Autoimmunreaktion Effektive Tolerisierungsstrategie. Studiendesigns welches geeignet ist den Effekt der Therapie auf den verlauf der Erkrankung und die immunologischen Mechanismen zu messen

19 IMMUNOLOGISCHE GRUNDLAGEN DER MULTIPLE SCLEROSIS 872 R. Hohlfeld Fig. 5 Crucial steps in multiple sclerosis pathogenesis. Pre-existing autoreactive T cells are activated outside the CNS. The activated T cells traverse the blood-brain-barrier and are locally re-activated when they recognize their antigen on the surface of local antigenpresenting cells. The activated T cells secrete cytokines that stimulate microglia cells and astrocytes, recruit additional inflammatory cells, and induce antibody production by plasma cells. Anti-myelin antibodies and activated macrophages/microglia cells are thought to cooperate in demyelination. See text for details. Modified from Gijbels (1995) with permission. Hohlfeld R, (1997). Brain 120,

20 Myelin-Proteine als Zielstruktur der CD4+ T cell reaktivität bei MS MC Mayer and E Mein Figure 1. Distribution of central nervous system (CNS) myelin proteins. A neuron with a myelinated axon Glial is depicted. potassium Myelin enwraps channel the axon (Kir at intervals 4.1)! called internodes omitting small openings termed nodes Ranvier. Adjacent to the nodes of Ranvier are the paranode and the juxtaparanode. All four zones have a Neurofascin! characteristic protein composition, as depicted in the upper part of the picture. At th nodes of Ranvier, Neurofascin Aquaporin 186 (NF186) supports 4! the clustering of Na+ channels. To allow saltatory conduction, the nodal Na+ channels are separated from the juxtaparanodal K+ channels via the paranode, where the myelin protein Neurofascin 155 Neuronal/axonal antigens, lipids..! (NF155) binds tightly to the axonal complex of Contactin-1 and Contactin-associated protein (Caspr). Connexins form gap junctions between myelin layers at the paranode cyclic-nucleotide 3 -phosphodiesterase (CNP) is an abundant cytoplasmic myelin protein, predominantly found at the paranode. At the juxtaparanode, clustered Myelin basic protein (MBP)! Proteolipid Protein (PLP)! Myelin associated glycoprotein (MAG)! Myelin oligodendrocyte glycoprotein (MOG)! Oligodendrocyte Surface Protein (OSP)!

21 Hypothese 1 Die autoreaktive T Zellen bei MS richten sich gegen eine einzelne Zielstruktur (Antigen)

22 Liste von berichteten Zielstrukturen bei MS MOG MBP p1-20 p11-30 p21-40 p35-55 p64-86 p p13-32 p83-99 p p p p p p PLP MAG p30-49 p41-58 p p p p p p p20-40 p41-63 p p p

23 Hypothese 1 Hypothese 2 Die autoreaktive T Zellen bei MS richten sich gegen eine einzelne Zielstruktur (Antigen) ABER! es gibt unterschiedliche Zielstrukturen (Antigene) in verschiedenen MS Patienten

24 4 PLP PLP PLP PLP T cell Reaktivitäten 2 gegen PLP in einzelnen MS Patienten über die Zeit 18 V. K. Tuohy et al BA 14 6 Stimulation index PLP PLP CDMS at 60 Wk PLP PLP PLP PLP PLP CDMS at 154 Wk PLP PLP Stimulation index C B PLP PLP CDMS at 60 Wk PLP C Week after onset of symptoms Figure 7. Emergence of PLP epitope spreading during progression of IMDS to CDMS. Over the course of the present study, two 2.0 PLP PLP PLP IMDS patients (VS, DL) showed progression to CDMS accompanied by the emergence of neo-autoreactivity. (A) VS showed secondary spreading responses 2.5 to PLP at 154 and 170 weeks and to both PLP and PLP at 170 weeks. Epitope spreading at onset of CDMS at 154 weeks was not accompanied by detectable proliferative responses to the PLP region implicated in the early onset stage of the disease. (B) DL showed disease progression at 60 weeks that was PLP Tuohy et al. JAI 1998

25 Hypothesis 1 Hypothesis 2 Hypothesis 3

26 Therapien die darauf abzielen Immuntoleranz zu induzieren sollten gleichzeitig gegen unterschiedliche Zielstrukturen (Antigen) gerichtet sein und die Fähigkeit haben die Ausbreitung der Immunantwort zu unterbinden. Hypothesis 2 X X X X X X X Hypothesis 3

27 Zielstrukturen zur Toleranzinduktion bei MS MOG MBP PLP p1-20 p13-32 p35-55 p83-99 p p p

28 ANTIGEN-COUPLED CELL TOLERANCE!"##$%&'(&$)&*#+,&-.!&/0102&3%*#$45!6##$7&$)&*#+,&8$##&9::67;#&/0<=2&>%$?;%"*7&$)&*#+,&8$##& /00L2&I$77$M4&$)&*#+,&-&9::67;#&/00=,&N*7&$)&*#+,&-&9::67;#&/00/&*7M&/00C&O*7M$%#6?)&$)& *#+,& -& 9::67;#& C===,& ':")P& $)& *#+,& -& H6);"::67& C==D2& '6& $)& *#+,& -& G$6%;"::67;#& /00/,& O*7M$7Q*%R&$)&*#+,&-&G$6%;KS"&T$K&/00D,&':*%%&$)&*#+,&N6%#$4&$)&*#+&-&9::67;#&C==1,&>$UK& $)&*#+,&-&9::67;#&C=//,&':*%%&$)&*#+,&-&9::67;#&C=//&

29 !"##$%&'(&$)&*#+,&-.!&/0102&3%*#$45!6##$7&$)&*#+,&8$##&9::67;#&/0<=2&>%$?;%"*7&$)&*#+,&8$##& /00L2&I$77$M4&$)&*#+,&-&9::67;#&/00=,&N*7&$)&*#+,&-&9::67;#&/00/&*7M&/00C&O*7M$%#6?)&$)& *#+,& -& 9::67;#& C===,& ':")P& $)& *#+,& -& H6);"::67& C==D2& '6& $)& *#+,& -& G$6%;"::67;#& /00/,& O*7M$7Q*%R&$)&*#+,&-&G$6%;KS"&T$K&/00D,&':*%%&$)&*#+,&N6%#$4&$)&*#+&-&9::67;#&C==1,&>$UK& $)&*#+,&-&9::67;#&C=//,&':*%%&$)&*#+,&-&9::67;#&C=//&

30 +9"FH"'4;(92*"!"#$ "%&'(%)*'+,$-+.),// &'#()(*+*" $"#",(-./0123" 4'#()(*+*" %$ &'&$()*+(,($ %$!"#$ -.&$()+)/$ -.&$0)+**$ -.&$(((+(/*$ -.&$(12+(34$ -56$(+/4$ -56$),+,,$ &'&$$()*+(,1$ %$ /" 0/-'8+9:" )(40;/9"!"#"!"#$ %$ <-48+21" 0/92)/8" =9>-*+/9" %"#" Innovative Therapieverfahren auf zellulärer und molekularer Basis

31 MULTIPLE SCLEROSIS Antigen-Specific Tolerance by Autologous Myelin Peptide Coupled Cells: A Phase 1 Trial in with Multiple ETIMS Sclerosis cell product Andreas Lutterotti, 1,2 Sara Yousef, 1 Andreas Sputtek, 3 Klarissa H. Stürner, 1 Jan-Patrick Stellmann, 1 Petra Breiden, 1 Stefanie Reinhardt, 1 Christian Schulze, 4 Maxim Bester, 5 Christoph Heesen, 1 Sven Schippling, 1,6 Stephen D. Miller, 7 * Mireia Sospedra, 1,6 *RolandMartin 1,6 * Multiple sclerosis (MS) is a devastating inflammatory disease of the brain and spinal cord that is thought to result from an autoimmune attack directed against antigens in the central nervous system. The aim of this firstin-man o trial was to assess the feasibility, safety, and tolerability of a tolerization regimen in MS patients that uses a single infusion of autologous peripheral blood mononuclear cells chemically coupled with seven myelin peptides (MOG 1 20,MOG 35 55,MBP 13 32,MBP 83 99,MBP ,MBP ,andPLP ). An open-label, singlecenter, dose-escalation study was performed in seven relapsing-remitting and two secondary progressive MS patients who were off-treatment for standard therapies. All patients had to show T cell reactivity against at least one of the myelin peptides used in the trial. Neurological, magnetic resonance imaging, laboratory, and immunological examinations were performed to assess the safety, tolerability, and in vivo mechanisms of action of this regimen. Administration of antigen-coupled cells was feasible, had a favorable safety profile, and was well tolerated in MS patients. Patients receiving the higher doses (> ) of peptide-coupled cells had a decrease in antigen-specific T cell responses after peptide-coupled cell therapy. In summary, this first-in-man clinical trial of autologous peptide-coupled cells in MS patients establishes the feasibility and indicates good tolerability and safety of this therapeutic approach. ale ple sis nts INTRODUCTION Approaches to induce antigen-specific tolerance in multiple sclerosis (MS) hold the promise to stop the pathogenic autoimmune response, thus preventing disease activity while avoiding the potentially severe side effects, which are associated with many of the currently used immunotherapies (1, 2). In MS, the primary target antigens are not known for certain, but it is well accepted that proteins within the myelin sheath, such as myelin basic protein (MBP), myelin oligodendrocyte protein (MOG), and proteolipid protein (PLP), are important targets of the autoreactive immune response (3). However, the target epitopes of myelin proteins differ between MS patients, and it is likely that the myelin-specific T cell reactivity may change over time (4 6). In relapsingremitting (RR) animal models of MS, chronic demyelination leads to the generation of new T cell responses against multiple endogenous antigens, a process called epitope spreading, and these newly generated T cells are able to induce relapses, which can be inhibited by tol- as erance to the spread epitope (7, 8). Therefore, it is reasonable to assume that the efficacy of antigen-specific therapies willdepend notonlyon aton cal atsia urent ng T2 ated n) 8, Characterization of blood cell populations after treatment As a supplementary measure to determine safety and tolerability of ETIMS treatment, several relevant immune cell populations were knowledge of the specific target antigens but also on the ability to block epitope spreading at an early stage and thereby stop diversification of T cell autoreactivity. Consequently, antigen-specific therapies should simultaneously target previously activated autoreactive T cells and also naïve autoreactive T cells specific for multiple myelin epitopes. Antigen-coupled cell tolerance is a tolerization strategy with a long-standing and excellent track regarding efficacy and safety in several experimental models of autoimmune diseases, transplantation tolerance, and allergic disease (9, 10). Antigen-specific tolerance is induced through carrier cells, which are pulsed with antigens in the presence of the chemical cross-linker 1-ethyl-3-(3-dimethylaminopropyl)- carbodiimide (EDC) (9, 11 15). Studies in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, have proven that a single intravenous injection of syngeneic splenocytes coupled with encephalitogenic myelin peptides/proteins is highly efficient in inducing antigen-specific tolerance in vivo (15 22). In EAE, this protocol not only prevented disease but also effectively reduced the onset and severity of all subsequent relapses when given after disease induction (17, 18, 23 25). As a major advantage of the therapy, tolerance can be simultaneously induced to multiple epitopes using a cocktail of myelin peptides (23). With the aim to induce antigen-specific tolerance in MS, we adopted Fig. 3. Clinical exacerbations after ETIMS treatment. Clinical exacerbations in the year before treatment (gray circles), during the first 3 months after 1 Institute for Neuroimmunology and Clinical MS Research, Center for Molecular Neurobiology, Hamburg, Germany. 2 Clinical Department of Neurology, Innsbruck Medical University, 6020 Innsbruck, Austria. 3 Institute of Transfusion Medicine, Center for Diagon June 5, 2013 Downloaded from stm.sciencemag.org e 5, 2013

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