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Transcript
Drugs that influence immune function Dr. Andrew Wiemer What is a drug? • A substance which has an effect when introduced into the body. – Substance – small molecule, macromolecule – Effect – therapeutic, prophylactic, recreational, performance enhancing – Body – a human, (or veterinary, or pathologic) What happens to a drug? • Pharmacokinetics – What is the fate of drug after administration? • Pharmacodynamics – How does the drug affect the body? https://gostardb.com/gostar/images/pharmacodynamicpharmacokinetic.jpg Drug targets are most often receptors • Classic receptor is on cell membrane – May also be intracellular or nuclear • Receptor binds to a ligand (agonist), which initiates a response • Can be non-receptors – Enzymes – Structural proteins – Nucleic acids Four major types of receptors Ion channels (~13%) G protein coupled receptors (~27%) Receptor tyrosine kinases (<2%) Nuclear receptors (~13%) http://pharmacologycorner.com Drugs can be classified based on their dosing, substance, or targeted species • Most current drugs are small molecules, but the fastest growing group of drugs is biologicals • Most biologics are immune related • Most drugs target humans, but some target pathogens • Most drugs are orally administered Overington et al., Nat Rev Drug Disc, 2006 Immunological drugs • Two broad approaches 1. Alter the function of immune system cells 2. Use the immune system to produce drugs Why alter function of immune cells? • Activate an immune response – Infectious disease – Cancer immunotherapy • Inhibit an immune response – Organ transplant – Autoimmune disease T cell activation Rudd, Nature Reviews Immunology 8, 153-160 9 T cell receptor signaling Adhesion molecules Receptors Co-receptors Relevant drug target Enzymes cytokines Vaccines https://apps.nlm.nih.gov/againsttheodds/exhibit/preventing_disease/role_of_science.cfm Vaccines http://hcrc.missouri.edu/2015/08/12/the-power-players-in-public-health/ Vaccines http://hcrc.missouri.edu/2015/08/12/the-power-players-in-public-health/ Checkpoint therapy • Seeks to overcome normal inhibitory signaling that prevents T cell activation • Ipilimumab – antibody to CTLA4 that breaks tolerance in cancer (FDA approved 2011) • Nivolumab – antibody to PD1 (FDA approved in 2014) http://www.onclive.com/publications/contemporary-oncology/2014/February2014/Immune-Checkpoint-Blockade-in-Cancer-Inhibiting-CTLA-4-and-PD1PD-L1-With-Monoclonal-Antibodies Transplant/immune disease Small molecule inhibitor • Cyclosporine (aka Neoral, Sandimmune, Restasis) • Immunosuppressant used in organ transplant • Also used in psoriasis, asthma, dry eye • Prevents dephosphorylation of NFAT, blocking T cell proliferation and cytokine production Cyclosporine Transplant/immune disease Antibody inhibitor • Muromonab-CD3 (OKT3) • Used in organ transplant • First monoclonal Ab approved for therapeutic use (1985) • Incorrectly activates T cells, preventing them from responding to graft Why use products of immune system as drugs? • Cytokines – Advantages • Boost immunity towards disease such as cancer – Disadvantage • Narrow therapeutic window – high doses can be toxic • Antibodies – Advantages • Specificity to target • Speed of production – Disadvantages • Oral dosing difficult • Trouble with intracellular targets Cytokines • Proleukin (FDA approved 1992) • Synthetic version of human IL-2 • Promotes proliferation of T cells, which can then kill tumor cells Therapeutic antibodies • Natalizumab (Tysabri) is an antibody to the integrin CD49d • Approved for treatment of multiple sclerosis (MS) • Prevents infiltration of immune cells into brain • Prevents migration across surfaces expressing VCAM such as endothelial cells http://www.rxlist.com/tysabri-drug/clinical-pharmacology.htm Therapeutic antibodies • Cetuximab • Representative of a class of antibodies that target growth factor receptors • Binds to extracellular domain III of EGFR • Blocks ability of EGF to bind EGFR • Prevents formation of extended conformation • Inhibits dimerization and autophosphorylation Li, 2005, Cancer Cell Therapeutic antibodies • Adalimumab (Humira) • Binds to soluble TNF alpha, preventing it from binding its receptor • Useful for treatment of RA, Crohn’s disease, psoriasis http://www.haderermuller.com/portfolio-item/inflammatory-bowel-disease/ Antibody drug conjugates • Brentuximab vedotin • Approved for lymphoma therapy • CD30 antibody • Monomethyl auristatin E • Cathepsin cleavage to activate Therapeutic antibodies • Summary – At least 5 different ways that monoclonal antibodies can function are shown here – All are extracellular targets – See Janeway Chapter 16? (manipulation of the immune response) Nature Reviews Immunology 10, 301-316 (May 2010)