2MB+Immunopharmacology+II+-+Approach+to+a+chronic+inflammatory+disease.pdf

Immunopharmacology II: Approach to chronic inflammatory or autoimmune disease Prof. L.J. Egan IBD RA Psoriasis IBD: Histology    Epithelium ulcerated Lamina propria infiltrated with acute and chronic inflammatory cells Crypt abscesses A multitude of factors in IBD Inflammatory bowel diseased Some...

Immunopharmacology II: Approach to chronic inflammatory or autoimmune disease Prof. L.J. Egan IBD RA Psoriasis IBD: Histology    Epithelium ulcerated Lamina propria infiltrated with acute and chronic inflammatory cells Crypt abscesses A multitude of factors in IBD Inflammatory bowel diseased Some drugs used to treat chronic inflammatory and autoimmune diseases  Immunosuppressants    Thiopurines Methotrexate Biologics     Anti-TNF Anti-integrin Anti-cytokine Anti-B cell IMMUNOSUPPRESSANTS Thiopurines    Azathioprine Originally developed as an anti-leukemia drug Pro-drug of 6-mercaptopurine Metabolism of Azathioprine and 6-Mercaptopurine Thiopurines: Mechanism of action  Deplete purine nucleotides  Inhibit    DNA synthesis RNA synthesis Results in   Apoptosis of activated lymphocytes Impaired cell-mediated immunity Azathioprine: Uses     Rheumatoid arthritis IBD Autoimmune hepatitis Prevention of transplant rejection Thiopurines: Administration & Adverse effects    Azathioprine or 6-mercaptopurine Oral, slow onset of action (months) Early ADRs      Allergy: Fever, skin rash Bone marrow suppression, esp. leukopenia Pancreatitis Opportunistic infections Late ADRs    Opportunistic infections Liver injury EBV-associated lymphomas Azathioprine – Thiopurine methyltransferase pharmacogenetics Very High 6TGN levels and high risk of myelosuppression High 6TGN levels and moderate risk of myelosuppression Nobel Prize 1988 Gertrude B. Elion Anti-metabolite drugs Which statement is false?      Azathioprine is a pro-drug Hereditary factors affect responses to thiopurines Azathioprine does not cause significant immunosuppression Thiopurines are administered orally Patients full blood count should be monitored Methotrexate Methotrexate: Classical mechanism      Competitive analog of folic acid Blocks dihydrofolate reductase Prevents accumulation of 4H-folic acid Blocks purine biosynthesis S-phase cells most sensitive Methotrexate: Mechanisms   Apoptosis of activated lymphocytes Inhibition of neutrophil functions Methotrexate: Clinical Pharmacology 1 0 0 0 M T X 7 O H M T X 1 0 0 Plasmconetraion,ml/ 1 0 1 0. 1 0 2 4 4 8 7 2 9 6 1 2 0 1 4 4 1 6 8 H o u r s p o s t m e t h o t r e x a t e 1 5 m g s. c. Erythrocyte methotrexate (nmol/L) Methotrexate: Clinical Pharmacology supports once weekly administration 15 mg/week 25 mg/week 350 300 250 200 150 100 Weeks after starting methotrexate 50 0 0 2 4 6 8 10 12 14 16 Methotrexate: Administration and adverse effects    Once weekly, oral, SC or IM Slow onset of action (weeks-months) Adverse effects    Bone marrow suppression (dose-dependent) Liver toxicity (fat and alcohol) Hypersensitivity pneumonitis (idiosyncratic) Which statement is true about methotrexate?      Methotrexate blocks accumulation of dihydrofolate It is structurally similar to purine nucleotides Methotrexate can only be administered parenterally Adverse effects include kidney damage Administered once weekly BIOLOGICS Biological Monoclonal Antibodies 180Da 150kDa acetylsalicylic acid monoclonal AB Kozlowski et al, NEJM 2011;365:385-8 Physical Features of IgG Recombinant Monoclonal Antibodies Biological characteristics Antigen binding Physicochemical characteristics N-terminal heterogeneity Amino acid modifications Hinge fragmentation Glycosylation Effector functions complement interaction Fc receptor interaction fucosylation, sialylation… Disulfide bond shuffling C-terminal heterogeneity Adapted from J. Windisch EAHP congress Milan, March 21-23, 2012 Monoclonal antibodies Advantages  Highly specific to their target  Long duration of action  Most side effects are intrinsic ie extensions of the action of the drug at its target  New drug targets available    Extracellular proteins Cell surface proteins Big in immune-mediated disease and oncology Disadvantages  Expensive  Parenteral administration  Immunogenicity  Infusion reactions Generation of monoclonal antibodies Generations of monoclonal antobodies PK of monoclonal antibodies: Absorption and distribution   Absorption: Parenteral injection only (IV or SC) Distribution:   Extravasation not dependent on passive diffusion Convection more important    Fluid flux Transcytosis via Fc receptors also relevant Antigen binding in tissues PK of monoclonal antibodies: Elimination    Receptor-mediated endocytosis Intracellular catabolism by lysosomal degradation Protective effect of FcRn leading to some recycling PK of monoclonal antibodies: Importance of immunogenicity   Mabs are foreign proteins and can be recognized as foreign by recipients immune system Induction of anti-drug immune response    Faster drug clearance and lower levels Loss of clinical efficacy Increased risk of allergic-type reactions Which statement about monoclonal antibodies is false?      They are highly selective in binding their target They are much more complex and costly to produce than small molecule drugs They must be administered parenterally (by injection) They are metabolized by cytochromes P450 in the liver They are dosed much less frequently than small molecule drugs TNF- is central in Pathogenesis of many diseases eg IBD, RA, psoriasis From Podolsky D et al 2006 Strategies to block TNF Anti-TNF antibodies Infliximab VL CH CL Human Fc Region Human FAB Arm Johnson & Johnson Ringaskiddy Golimumab Human FAB Arm Mouse FAB Arm VH CL Adalimumab Human Fc Region Mouse FAB Region Certolizumab pegol Human Fc Region I-125 Anti-ICAM-1 bound cpm Infliximab potently neutralizes TNF- 15 000 B Control Ig 10 000 5000 Infliximab 0 1 10 100 1000 10 000 IgG, ng/Ml TNF- induced ICAM-1 production from HUVEC Siegel S et al 1995 Infliximab-induced suppression of cytokine production and induction of apoptosis Infliximab Reverse Signalling Infliximab Human Human Mouse Mouse tmTNF tmTNF FADD Bak Bax Nucleus Cytokine Suppression TNF-α IL-12 IL-10 Caspase 8 Caspase 9 Caspase 3 TNF producing cell Figure 2: Reverse signalling due to the binding of a TNF antagonist to membrane bound TNF trimer. TNF producing cell Apoptosis Effect of immunogenicity Etanercept      Soluble TNF receptor fusion protein Affectively neutralises biological activity of TNF Does not bind to membrane associated TNF Does not induce apoptosis of TNF expressing cells Effective in RA but not IBD Pfizer Grangecastle Adverse Effects of TNF Inhibitors  Class Effects     Reactivation of latent tuberculosis Increased risk of opportunistic infections Emergence of Multiple Sclerosis Injection and infusion reactions True statements concerning anti-TNF biologics include      Infliximab is a mouse-human chimeric anti-TNF monoclonal antibody Patients should be screened for latent tuberculosis before starting any anti-TNF drug Loss of response to anti-TNF biologics is often due to their immunogenicity These drugs have proved highly beneficial in treating several chronic inflammatory diseases All of the above Anti-integrin biologics: Leukocyte extravasation inhibitors Natalizumab: anti-α4 integrin Vedolizumab: specific anti-α4β7 integrin Anti-cytokine biologics  IL-12/23     Derived from many types of immune cells Elevated in many inflammatory diseases Stimulate Th1 and Th17 signalling Ustekinumab  Monoclonal anti-p40 subunit Anti-B lymphocyte biologics    B cells involved in pathogenesis of RA B cell malignancies ie lymphoma common Rituximab    Anti-CD20 monoclonal Blocks B cell activation Kills B cells by multiple mechanisms Similarities and Differences in approach to some chronic inflammatory, autoimmune diseases and organ transplant Inflammatory Bowel disease Rheumatoid arthritis Psoriasis Multiple sclerosis Organ transplant Corticosteroids Yes Yes Yes Yes Yes Methotrexate Yes Yes Yes No No Thiopurines Yes Yes No No Yes Anti-TNF biologics Yes Yes Yes No No Anti-integrin biologics Yes No No Yes No Anti-IL-12/23 biologics Yes No Yes No No Anti-lymphocyte No biologics Yes No No Yes mTOR inhibitors No No No Yes No