Merck KGaA · XETR:MRK
Merck KGaA — acadeMe MS Annual Conference Virtual Series 2022
43 slides from Merck KGaA's conference presentation, Apr 20, 2022
Slide 1: The innate immune system and MS: A journey from disease initiation to progression
acadeMe MS ANNUAL CONFERENCE VIRTUAL SERIES The innate immune system and MS: A journey from disease initiation to progression 20 April 2022 18:00–19:00 CEST GL-NONNI-01307 This Medical Education program is funded and organized by Merck. The information included in this program are intended for educa
Slide 2: Welcome and objectives
Welcome and objectives Prof. Xavier Montalban
Slide 3: Our faculty and their disclosures
Our faculty and their disclosures Prof. Xavier Montalban Prof. Jorge Correale Prof. Luisa Klotz Multiple Sclerosis Centre of Catalonia Institute for Neurological Research Dr. Raul Department of Neurology, University of (Cemcat), Spain Carrea (FLENI), Argentina Münster, Germany Professor Montalban ha
Slide 4: acadeMe-MS.com
acadeMe-MS.com A knowledge forum for healthcare professionals with a focus on development, access and exchange of best-in-class knowledge about MS To find out more about the latest events and access online educational content and resources, visit acadeMe-MS.com
Slide 5: Learning objectives
Learning objectives By the end of this meeting, participants will be able to: 1 Define the role of key innate immune cells in the pathogenesis of MS Describe the effects of approved DMTs and investigational agents on cells of the innate 2 immune system Explain the potential role of innate-targeting
Slide 6: Agenda
acadeMe MS annual conference virtual series Agenda Time (CET) Session Speaker(s) 18:00–18:05 Welcome and introductions Prof. Xavier Montalban 5 mins 18:05–18:15 Innate immune system basics: Introduction to the function of key cells Prof. Jorge Correale 10 mins 18:15–18:25 The role of the innate immu
Slide 7: Innate immune system basics: Introduction to the function of key cells
Innate immune system basics: Introduction to the function of key cells Prof. Jorge Correale
Slide 8: The innate immune system is a first-line defence against pathogens
The innate immune system is a first-line defence against pathogens Innate immunity is a first-line non-specific (antigen-independent) defence mechanism against intruding pathogens1 Primary function of the innate Bacteria immune system: • First-line defence against common microorganisms2 Dendritic In
Slide 9: The innate and adaptive immune responses
The innate and adaptive immune responses Innate Figure adapted from Dranoff G 2004.1 Adaptive (rapid response) Courtesy of Prof. Correale (slow response) B cell T cell Dendritic Mast cell cell C1q Macrophage 𝛾𝛿 T cell Basophil Complement C1r2s2 Natural killer cell R Complement Eosinophil Natural…
Slide 10: Innate cells drive key immunologic processes in the CNS and periphery
Innate cells drive key immunologic processes in the CNS and periphery Example schematic of innate cell involvement in an immune response A Periphery Pathogen type Draining lymph node Th1 T cell Inflamed tissue decoded Processed antigen IFN-𝛾 Bacterium We will explore key Th2 T cell Resident innate…
Slide 11: Microglia functions
Microglia functions Periphery Pathogen type Draining lymph node Th1 T cell Inflamed tissue decoded Processed antigen IFN-𝛾 Bacterium Th2 T cell Resident macrophage Dendritic cell Macrophage IL-4 Virus Microglia Naïve T cell Th17 T cell Protozoan Monocyte Polarising Recruited Natural killer cell…
Slide 12: Astrocyte functions
Astrocyte functions Periphery Pathogen type Draining lymph node Th1 T cell Inflamed tissue decoded Processed antigen IFN-𝛾 Bacterium Th2 T cell Resident macrophage VirusAstrocytes Dendritic cell Macrophage IL-4 Naïve T cell • Regulate the immune response Protozoan in the CNS and Monocyte Polarising
Slide 13: Mast cell functions
Mast cell functions Periphery Pathogen type Draining lymph node Th1 T cell Inflamed tissue decoded Processed antigen IFN-𝛾 Bacterium Th2 T cell Resident macrophage Virus Mast cells Dendritic cell Macrophage IL-4 Naïve T cell Th17 T cell Polarising • Proinflammatory Protozoan cells that Natural are…
Slide 14: Monocyte function
Monocyte function Periphery Pathogen type Draining lymph node Th1 T cell Inflamed tissue decoded Processed antigen IFN-𝛾 Bacterium Th2 T cell Resident Monocytes macrophage Dendritic cell Macrophage IL-4 Virus Naïve T cell • Phagocytose Protozoan and present antigens, Monocyte secrete Polarising…
Slide 15: Natural killer cell functions
Natural killer cell functions Periphery Pathogen type Draining lymph node Th1 T cell Inflamed tissue decoded Processed antigen IFN-𝛾 Bacterium Th2 T cell Resident macrophage Virus Dendritic cell Macrophage Natural killer cells IL-4 Naïve T cell Protozoan Natural killer cell Monocyte Polarising •…
Slide 16: Dendritic cell functions
Dendritic cell functions Periphery Pathogen type Draining lymph node Th1 T cell Inflamed tissue decoded Processed antigen IFN-𝛾 Bacterium Th2 T cell Resident macrophage Virus Dendritic cell Macrophage Dendritic cells IL-4 Naïve T cell Protozoan Natural killer cell Monocyte Polarising • Phagocytose…
Slide 17: Macrophage functions
Macrophage functions Periphery Pathogen type Draining lymph node Th1 T cell Inflamed tissue decoded Processed antigen IFN-𝛾 Bacterium Th2 T cell Resident Macrophages macrophage Dendritic cell Macrophage IL-4 Virus Naïve T cell • Phagocytose bacteria and secrete Protozoan Monocyte Polarising Th17 T…
Slide 18: Neurons, astrocytes and microglia interact in the CNS to maintain homeostasis
Neurons, astrocytes and microglia interact in the CNS to maintain homeostasis1 Diseased brain: stress, injury, Healthy brain maldevelopment, neurodegeneration Healthy neurons regulate activation of glial cells. Homeostasis is disrupted under diseased conditions. Neurons deliver damage Neuron Neuron
Slide 19: Innate cells have diverse roles under homeostatic and neuroinflammatory conditions
Innate cells have diverse roles under both homeostatic and neuroinflammatory conditions Healthy brain Peripheral immunity Neuroinflammation Blood–brain barrier: Absolute CNS–resident immune cells immunological barrier Infiltrating • Microglia Parenchyma peripheral • Border-associated macrophages Imm
Slide 20: Summary
Summary Innate cells drive Individual innate immune cell Interactions involving key immunologic processes types can exhibit diverse innate immune cells are critical in the CNS and periphery. functions, acting in both for homeostasis of the CNS. inflammatory and regulatory ways. CNS, central nervous
Slide 21: The role of the innate immune system in the pathogenesis of MS
The role of the innate immune system in the pathogenesis of MS Prof. Luisa Klotz
Slide 22: Emerging role of the innate immune system in MS
Emerging role of the innate immune system in MS
Slide 23: Emerging role of the innate immune system in MS
Emerging role of the innate immune system in MS1–14 Pathophysiology of MS Oligoclonal antibodies B cells Microglia Memory T cells Astrocytes Memory B cells Plasma cells T cells Macrophages Spotlight on immune cells during the study of MS 1950s TODAY 1. Winger RC and Zamvil SS. Proc Natl Acad Sci USA
Slide 24: Microglia and macrophages contribute to neurodegeneration
Microglia and macrophages contribute to neurodegeneration
Slide 25: Microglia and macrophages are important players in neurodegeneration
Microglia and macrophages are important players in neurodegeneration1,2 Activated microglia and macrophages Activation of microglia Stimulation of astrocytes and macrophages are and microglia by TLR Cytokine release found in acute MS lesions ligands promote secretion Reactive and persist in chronic
Slide 26: Macrophages activate in response to local inflammation
Macrophages activate in response to local inflammation1,2 Choroid plexus Meninges (blood–CSF barrier) (blood–brain barrier) Choroid plexus macrophage Dura mater Arachnoid mater mater Meningeal and choroid plexus Arachnoid Subarachnoid space (CSF) BAMs are key to defining MS lesion types:2 Meningeal
Slide 27: Microglial subsets are diverse and can be enriched for genes involved in MS
Microglial subsets are diverse and can be enriched for genes involved in MS1 Microglial subsets: A closer look at microglia roles in MS: Single-cell RNA sequencinga has shown some microglial subsets Classically activated microglia are implicated (‘clusters’) are enriched for genes involved in MS1 in
Slide 28: Microglia and macrophages are involved in active MS lesions from the earliest stage
Microglia and macrophages are involved in active MS lesions from the earliest stage1 Patterns of microglia and macrophage Monocyte-derived macrophages characteristics over time in different MS lesion types1 contribute to tissue destruction2,3 Microglia/macrophage density Ramification (complex, highl
Slide 29: Other cells of the innate immune system in MS
Other cells of the innate immune system in MS
Slide 30: Additional innate immune cell types contribute to MS
Additional innate immune cell types contribute to MS1–8 CD4+ T cell CD8+ T cell Dendritic cell Natural killer cell Periphery B cell Mast cells (blood) Accumulate in MS plaques and NAWM and contribute to BBB neurodegeneration by disrupting the BBB and recruiting peripheral CNS Glia limitansa monocyte
Slide 31: Summary
Summary MS pathology involves both Macrophages and microglia Further distinguishing innate innate and adaptive immune have key roles in MS cell involvement in MS cells, acting at peripheral and neurodegeneration is an area of central sites ongoing research
Slide 32: DMTs and innate immunity: Current and future perspectives
DMTs and innate immunity: Current and future perspectives Prof. Xavier Montalban
Slide 33: DMTs and innate immunity: Current perspectives
DMTs and innate immunity: Current perspectives
Slide 34: There are no approved DMTs designed to target cells of the innate immune system
There are no approved DMTs designed to target cells of the innate immune system1–15 Glatiramer acetate4 Alemtuzumab7 Ocrelizumab10 Ofatumumab14 Dimethyl sc IFN β-1b1 im IFN β-1a2 Natalizumab5 Fingolimod6 fumarate9 Siponimod12 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2017 2018 2019 2020
Slide 35: There are no approved DMTs designed to target cells of the innate immune system
There are no approved DMTs designed to target cells of the innate immune system1–15 However, some innate cell Glatiramer acetate4 populations are impacted Alemtuzumab7 Ocrelizumab10 Ofatumumab14 by DMTs Dimethyl sc IFN β-1b1 im IFN β-1a2 Natalizumab5 Fingolimod6 fumarate9 Siponimod12 NK cells NK cel
Slide 36: Approved DMTs can indirectly impact NK cell populations
Approved DMTs can indirectly impact NK cell populations Alemtuzumab Cladribine tablets Dimethyl fumarate Fingolimod Natalizumab Expanded the CD56bright Transiently depleted NK cells to a Increased mean absolute NK Decreased the proportion of Increased total NK cells and NK cell subset1 maximum of 50
Slide 37: The effect of DMTs on microglial activation
The effect of DMTs on microglial activation Microglial activation was measured one year after natalizumab treatment with PET imaging in RRMS patients1 Natalizumab treatment reduced microglial activation Higher microglial activation in NAWM and in NAWM and at the rim of chronic lesions1 perilesional
Slide 38: DMTs and innate immunity: Future perspectives
DMTs and innate immunity: Future perspectives
Slide 39: CNS-resident innate immune cells are a promising target in MS
CNS-resident innate immune cells are a promising target in MS1 Lymph node S1P blockers Brain Trophic or antioxidant neuronal support Neurons DHODH inhibitorsa BTK inhibitors CD52 immune Microglia cell elimination CD20 B-cell Enhanced elimination Interferons, glatiramer remyelination acetate, fumarat
Slide 40: BTK is involved in both adaptive and innate immune processes
BTK is involved in both adaptive and innate immune processes1 BBB PERIPHERY CNS BTK is expressed in BTK is expressed in memory B cells and B cells microglia and a macrophages2–3 subset of astrocytes4 Follicular Ex vivo and animal models B cells Ex vivo • Increased microglial BTK expression has been
Slide 41: Inhibiting BTK activation in cells that mediate neuroinflammation may reduce MS progression
Inhibiting BTK activation in cells that mediate neuroinflammation may reduce MS disease progression1,2 BBB PERIPHERY CNS BTK Macrophages B cells BTK BTK BTK Microglia T cells Astrocytes Figure adapted from Gruber et al. Neurology 20213 BBB, blood–brain barrier; BTK, Bruton‘s tyrosine kinase; CNS, ce
Slide 42: A range of BTK inhibitors are in clinical development for MS
A range of BTK inhibitors are in clinical development for MS1,2 BTKi Binding mechanism Clinical phase Evobrutinib (Merck KGaA) Covalent, irreversible 3 Fenebrutinib (Roche) Non-covalent, reversible 3 Remibrutinib (Novartis)2 Covalent2, irreversible1 32 Tolebrutinib (Sanofi) Covalent, irreversible 3
Slide 43: Summary
Summary There are no approved DMTs NK cells and microglia are Ongoing clinical studies designed to target cells of the populations of innate cells that investigate BTKi potential as innate immune system have been indirectly impacted part of the future treatment by some approved DMTs landscape for MS
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