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Slide 1 - New Treatments for Rheumatoid Arthritis Presented by: Ariel Kwan Christine Terzievski Rebecca Babaei-Rad Vivian Tsoi Course: Biochem PHM142 Presented on: Oct 23, 2013 PHM142 Fall 2013 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson
Slide 2 - What is Rheumatoid Arthritis (RA)? an immune-mediated, progressive disease CD4+ T-cells, activated B-lymphocytes, and plasma cells/macrophages are present in the synovium of patients diagnosed with RA Cytokine secretion by these activated cells leads to an inflamed synovium and the formation of pannus – leading to joint destruction
Slide 3 - Pathogenesis of RA
Slide 4 - Current Therapy of RA NSAIDs, glucocorticoids DMARDS as methotrexate,leflunomide, plaquenil, sulfasalazine Newer biological agents with specific molecular targets in RA pathogenesis: TNF-α antagonist/inhibitor Interleukin (IL) inhibitor and receptor antagonist B cell inhibitor (anti-CD20 antibodies) T cell directed therapies New molecules targeting JAKs
Slide 5 - What is TNFα?
Slide 6 - TNF-α Inhibitor TNF-α inhibitor binds TNF-α and prevents its interaction with its receptors Many are monoclonal antibodies, some are receptor fusion proteins Therapeutic goal is the removal of TNF-α from inflammation sites The first clinically successful, cytokine-specific therapy for RA (Lasker Award 2003) Used in combination with a DMARD Rapid onset of action (expected effect or improved symptoms in 1-3 weeks)
Slide 7 - Mode of TNFα Inhibitor Action
Slide 8 - TNF-α Inhibitor Drugs
Slide 9 - Adverse Effects of TNF-α Inhibitors Injection site reactions Increased risk of bacterial, viral, and/or fungal infections Bone marrow suppression Generation of antibodies to drugs, resulting in reduced efficacy over time Drug-induced lupus-like syndromes Emergence of lymphoma and skin cancers over long-term use
Slide 10 - Interleukins The body’s immune response involves the activation and release of cytokines (messengers) such as TNF and interleukins, from macrophages Leukocytes release a variety of interleukins to communicate with additional leukocytes (hence the name) Perpetuate the immune response (inflammation) IL-1 and IL-6 are particularly important as these the both involved in some way with inflammation of the joints Macrophage  IL-6 Macrophage and T-cells  IL-1 10
Slide 11 - Interleukin Receptor Inhibitors Usually only used if patient has not improved after using other anti-inflammatory medication such as TNF antagonists Should not be given while still using TNF antagonists due to adverse reactions that have been observed 11
Slide 12 - Tocilizumab Generic Name: Tocilizumab Brand Name: Actemra Interleukin receptor inhibitor, specifically for IL-6 binding Given intravenously on a per month basis Dosage: usually 20mg/ml Adverse Effects Include: risk of contracting tuberculosis, reduced platelet level in blood, risk of hypertension 12
Slide 13 - Tocilizumab Mode of Action Drug binds IL-6 receptors Prevents cytokine IL-6 from binding receptor Cell-to-cell communication is inhibited Inhibits production of more T and B cells and aids to decrease inflammation at the joints 13
Slide 14 - Interleukin Receptor Inhibitors In areas of body where IL are seen to be uncontrolled and released with no threat from invader, intensive tissue damage can be seen IL receptor inhibitors have proved to be quite successful in individuals with RA in relieving inflammation Additionally, shown to have beneficial effect on preventing bone degradation in RA patients as well 14
Slide 15 - B-Cell Inhibitors B-Cell Type of lymphocyte Produces antibodies Express Fc receptors Express CD20 on cell surface Phosphoprotein Spans the membrane four times Little known except it might function as a Ca2+ ion channel
Slide 16 - B-Cell Inhibitors Why target B-cells? Evidence for production of rheumatoid factor (RF) Autoantibody which binds to Fc region of IgG Depletion of B-cells is accompanied by reduction of inflammation Secrete cytokines which interact with cells involved in autoimmune response Ie. TNF-alpha and chemokines How to target B-cells? CD20 Found exclusively on B-cells Not shed from B cells Expressed at high levels
Slide 17 - B-Cell Inhibitors Rituximab Chimeric/fusion protein Antibody consisting of human IgG-1 constant regions and murine (mouse) variable regions Mouse variable regions come from antibody that recognizes CD20 Also binds to Fc receptors
Slide 18 - B-Cell Inhibitors Complement-dependent cytotoxicity (CDC) Innate immunity C1q Serum protein which binds to Fc region rituximab Triggers cascade resulting in C5b C5b triggers membrane attack complex (MAC) formation MEC forms transmembrane channels in the bilayer resulting in cell lysis
Slide 19 - Complement-dependent cytotoxicity
Slide 20 - B-Cell Inhibitors Antibody-dependent cell-mediated cytotoxicity (ADCC) Adaptive immunity Natural killer (NK) cells, granulocytes, macrophages all express Fc receptors of IgG Once bound, lyse B-cell using respective effector mechanisms Induction of apoptosis Little known about specifics
Slide 21 - 21 T-Cell Directed Therapy T-cell Type of lymphocyte Have a T-cell receptor on its surface Various types, including cytotoxic, helper, natural killer, memory, and regulatory Cytotoxic T cells destroy infected cells Also known as CD8+T cells because they express CD8 protein on the cell surface Bind to an antigen associated with MHC Class I 18
Slide 22 - 22
Slide 23 - 23 T-Cell Activation T-cell activation requires 2 signals: 1st signal: The antigen presented by the MHC is recognized by the T-cell receptor 2nd signal: Co-stimulatory molecules CD80 and CD86 on APCs bind to CD28, an auto-regulatory protein, on the T-cell surface T-cells have an intrinsic mechanism to terminate T-cell activation, which regulates immune activation
Slide 24 - 24 Regulating T-cell Activation T-cell regulation occurs via the Cytotoxic T-Lymphocyte Associated Antigen-4 (CTLA-4) molecule CTLA-4 acts as a negative regulator of CD28-mediated T-cell stimulation Antagonizes the CD80/CD86:CD28 binding pathway by binding CD80/CD86 Greater affinity for CD80/CD86 than CD28 Leads to the down-regulation of T-cell activation
Slide 25 - 25 Abatacept Classified as a biological disease-modifying anti-rheumatic drug (DMARD) Used to treat RA in patients who had failed to respond to other DMARDs or TNF inhibitors Consists of the extracellular domain of CTLA-4 and a modified Fc fragment of IgG1 to prevent antibody dependent cell-mediated cytotoxicity Has a novel mechanism of action that mimics CTLA-4’s action 22
Slide 26 - 26 Mechanism of Action Abatacept interrupts the CD80/CD86: CD28 pathway i.e. It does not allow the 2nd signal in T-cell activation to occur Abatacept binds to co-stimulatory proteins CD80 and CD86, preventing CD28 from binding Thus, T-cell activation is inhibited 23
Slide 27 - 27 Effects of Abatacept Inhibits the proliferation of T-cells in vitro and in vivo Reduces the amount of circulating CD8+CD28- T cells, which suppresses the number of CD4+T cells produced Reduces adhesion and migratory capacity of monocytes and the inflammatory activity of synovial macrophages Regulates the function of CD4+T cells 24
Slide 28 - 28 Overview of Abatacept’s Mechanism of Action
Slide 29 - 29 Janus Kinase Inhibitors (JAKs) New molecular approach to treating RA Inhibit the activity of the janus kinase (JAK) family to down regulate inflammatory reactions JAK inhibitors include: Tofacitinib VX-509 (Vertex) Baricitinib
Slide 30 - 30 JAK Family Tyrosine kinase proteins Family includes: JAK1 JAK2 JAK3 TYK2 Plays an important role in mediating the intracellular signal transduction of cytokines
Slide 31 - 31 Acting in pairs, JAK proteins facilitate the phosphorylation of intracellular proteins Phosphorylation of the signal transducer and activator of transcription (STAT) leads to altered gene transcription STAT controls autoimmune and inflammatory responses 26 JAK Proteins
Slide 32 - 32 Tofacitinib Small, non-biologic DMARD with demonstrated efficacy in treating RA Interferes with the signalling pathways of JAK1 and JAK3 JAK3 associates with the Ɣ-chain of common cytokine receptors These receptors are used by interleukins to regulate lymphocyte activation and production Inhibition leads to anti-inflammatory and immunosuppressive effects
Slide 33 - 33 Tofacitinib: Inhibiting JAK-Dependent STAT Pathways
Slide 34 - Summary
Slide 35 - Summary of RA Treatment RA is an auto-immune disease with upstream mechanisms of activated macrophages, activated B cells and activated T cells; resulting in downstream cytokine production and destruction signaling pathways. Activated macrophages secrete (downstream) inflammatory cytokines TNF-α, and IL-6 and IL-1. TNF-α inhibitors  etanercept, infliximab, adalimumab IL-6 receptor antagonist  tocilizumab IL-1 receptor antagonist  anakinra Activated B cells contribute to inflammation and destruction by producing autoantibodies (RF) and cytokine IL-6 Bind to CD20 antigen on B Cell and depletes B cells  rituximab Activated (CD4+) T cells activate macrophages and B cells Upstream regulation of T Cell activation pathway  abatacept Downstream signaling pathways (RANK, MMPs) JAK inhibitors to down regulate inflammatory responses  tofacitinib 35
Slide 36 - References Actemra. E-Therapeutics [Internet]. Canadian Pharmacists Association. 2013. [cited 2013 Sept 21] Available from: https://www-e-therapeutics-ca.myaccess.library.utoronto.ca/cps.select.preliminaryFilter.action?simplePreliminaryFilter=tocilizumab# Borker A and Choudhary N. Rituximab. Indian Pediatrics 48(8): 627-632, 2011. Choy EHS et al. Therapeutic benefit of blocking interleukin-6 activity with an anti-iinterleukin-6 receptor monoclonal antibody in rheumatoid arthritis. Arthritis and Rheumatism 46(12): 3143-3150, 2002. Colmegna et al. Current Understanding of Rheumatoid Arthritis Therapy. Clinical Pharmacology & Therapeutics 91(4): 607- 620, 2012. Feist E and Burmester GR. Small molecules targeting JAKs – a new approach in the treatment of rheumatoid arthritis. Rheumatology 52: 1352-1357, 2013. Flieger D et al. Mechanism of cytotoxicity induced by chimeric mouse human monoclonal antibody IDEC-C2B8 in CD20-expressing lymphoma cell lines. Cellular Immunology 204(1): 55-63, 2000. Garrett RH and Grisham CM. 2010. Biochemistry, fourth edition. Boston, Massachusetts: Brooks/Cole. 1059 p. Keating GM. Abatacept: A review of its use in the management of rheumatoid arthritis. Drugs 73: 1095-1119, 2013. Kubo S, et al. The JAK inhibitor, tofacitinib, reduces the T cell stimulatory capacity of human monocyte-derived dendritic cells. Ann Rheum Dis. 0: 1-7, 2013. Kwan-Morley J and Albert D. B-cell inhibitors as therapy for rheumatoid arthritis: an update. Current Rheumatology Reports 9(5): 401-406, 2007.
Slide 37 - Larrick JW. Native interleukin 1 inhibitors. Immunology Today 10(2): 61-66, 1989. Li H et al. Store-operated cation entry mediated by CD20 in membrane rafts. The Journal of Biological Chemistry 278(43): 42427-42434, 2003. Mola EM et al. Abatacept use in rheumatoid arthritis: evidence review and recommendations. Rheumatol Clin. 1: 5-17, 2013. Najafian N, et al. Regulatory functions of CD8+CD28- T cells in an autoimmune disease model. J Clin Invest. 112: 1037-48, 2003. Pappas DA et al. Immune modulation of rheumatoid arthritis. Best Practice & Research Clinical Rheumatology 25: 873-889, 2011. Rezvani AR and Maloney DG. Rituximab resistance. Best Practice and Research Clinical Haematology 24(2): 203-216, 2011. Scott DL et al. Rheumatoid arthritis. The Lancet 376(9746): 1094-1108, 2010. Shaw T et al. B-cell therapy for rheumatoid arthritis: the rituximab (anti-CD20) experience. Annals of the rheumatic diseases 62(2): ii55-ii59, 2003. Tayar JH and Suarez-Almazor ME. New understanding and approaches to treatment in rheumatoid arthritis. British Medical Bulletin 94: 201-204, 2010. Willey, J.M., Woolverton, C.J., Sherwood, L.M. (2011). Prescott’s Microbiology (8th ed.). New York, NY: McGraw-Hill. 37 References
Slide 38 - Image Credits (in order of appearance in presentation) http://www.medscape.org/viewarticle/505489_3 http://www.sciencedirect.com/science/article/pii/S0264410X13009110 http://www.leidenuniv.nl/en/researcharchive/index.php3-c=446.htm www.remicade.com http://3scorporation.com/products/actemra-80-mg-vial-5-ml/ http://www.actemrahcp.com/about-actemra/actemra-moa.html http://www.sciencedirect.com/science/article/pii/S1471489210000068 http://archive.ispub.com/journal/the-internet-journal-of-rheumatology/volume-5-number-2/management-of-inadequate-response-to-tnf-antagonist-therapy-in-rheumatoid-arthritis-what-are-the-options.html#sthash.LcCZjZcm.dpbs 38
 

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