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Workshop on Using the Guide to Immunoipharmacology. PDF of slides presented at BPS Pharmacology 2019 by Dr. Simon Harding.

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  2. 2. Overview • Development/Curation of the Guide to IMMUNOPHARMACOLOGY • Database Content • How to view immuno-relevant content • Portal • Target & Ligand Data • Target Data via immunological processes and cell types • Accessing data on case study on cardiovascular inflammation • Disease Summary Pages • Advanced Search WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 2
  3. 3. 3WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG The IUPHAR Guide to IMMUNOPHARMACOLOGY Developed to deliver a knowledge-base that connects immunology with pharmacology GtoImmuPdb is a Wellcome Trust-funded extension to the existing GtoPdb 1. Extended GtoPdb to contain key immunological data types and associate these with existing targets and ligands 2. Developed a new portal to provide an immunologist-friendly access-point to the data to allow easy browsing and searching 3. Continuing to curate new targets and pharmacological interactions
  5. 5. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 5 Developing the Guide to IMMUNOPHARMACOLOGY GtoP Database IUPHAR/BPS Guide to IMMUNOPHARMACOLOGY (GtoImmuPdb) Curation • Supported by NC-IUPHAR expert subcommittees • Tag relevant targets and ligands already in GtoPdb • Extended coverage to identify targets/ligands involved in inflammation/immunity • Curate associations between targets/ligands and immunological processes, cell types and disease
  6. 6. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 6 Database content GtoPdb GtoImmuPdb Human targets 2,937 578 Human targets with curated interactions 1,788 536 Ligands 9,700 1,213 Ligands with curated interactions 8,516 1,097 Approved Drugs 1,449 268 Antibodies 264 157 30% of targets with curated interactions are immune- relevant
  7. 7. Overview • • • How to view immuno-relevant content • Portal • Target Data & Ligand Data • • • • WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 7
  8. 8. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 8 Portal Panels to browse to target and ligand lists by category Database search Menu-bar
  10. 10. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 10 Target Data • Immuno-relevant families are highlighted • Target summary can be displayed • Link to detailed page
  11. 11. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 11 Target Data – Detailed View • Extensive data on the protein target • Properties, structure, ligands, references etc. • Immunopharmacology data is highlighted
  12. 12. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 12 Ligand Data • The database organises ligands by type and/or category. • Specific immuno category for ligand curated as immunologically relevant • Ligand summary pages contain the key information on biological activity, clinical use, molecular properties and structure.
  14. 14. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 14 Ligand Summary Pages Summary tab describes the ligand, its ‘type’, synonyms, whether it’s an approved drug, and links to external resources Clinical data tab contains curated information about clinical use and molecular mechanism of action.
  15. 15. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 15 Ligand Summary Pages Biological activity and Immunopharmacology tabs contain curated information about the ligand’s pharmacology and immunological context
  16. 16. Overview • • • How to view immuno-relevant content • • • Target Data via immunological processes and cell types • • • WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 16
  17. 17. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 17 Target data via immunological processes • Clear connections between immunological processes and targets in the database • Top-level categories – such as T cell activation, underpinned by GO biological processes, such as T cell mediate immunity. • Ontologies provide a controlled vocabulary to annotate data. Also good for interoperability. 11 top-level process categories 471 distinct child-terms 196 unique GtoPdb targets with annotations against these terms Source: UniProt
  18. 18. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 18 Target data via immunological processes • Link for each category list all associated targets • Organised by target class – with quick links • Drop-down menu to switch process category
  19. 19. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 19 Target data via immunological processes • Each target links through to detailed view page • Annotated GO process terms are listed • Detailed immunopharmacology curators comments also displayed.
  20. 20. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 20 Target data via immunological processes Role of CD28 in activation, proliferation and survival of T cells is highlighted
  21. 21. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 21 Target data via immunological cell type • Clear connections between immunological cell types and targets in the database • Top-level categories underpinned by Cell Ontology terms. 10 top-level cell type categories
  22. 22. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 22 Target data via immunological cell type 10 top-level cell type categories • Clear connections between immunological cell types and targets in the database • Top-level categories underpinned by Cell Ontology terms.
  23. 23. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 23 Target data via immunological cell type Pharmacology data for NKG2A (CD159a) – expressed in NK cells • Role of natural killer cells in anti-tumour immunity • NKG2A (CD159a) known to functions as a checkpoint in NK cell activation
  24. 24. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 24 Target data via immunological cell type Pharmacology data for NKG2A(CD159a) – expressed in NK cells • Comments highlight role as an inhibitory checkpoint receptor for HLA-E
  25. 25. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 25 Target data via immunological cell type • Detailed view shows pharmacological interaction data with antibody monalizumab – an anti- NKG2A clinical lead molecule.
  26. 26. Overview • • • How to view immuno-relevant content • • • • Accessing data on a case study on cardiovascular inflammation • • WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 26
  27. 27. Case study: targeting cardiovascular inflammation 27WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG • Experimental data shows a causal role by immune and inflammatory responses in the initiation and development of atherosclerosis, but there are no immunomodulatory treatments in routine use. • The CANTOS Phase 3 trial was the first to demonstrate that blockade of the IL-1β innate immune pathway could achieve clinical efficacy in reducing recurrent cardiovascular events in at risk patients • Ridker et al. (2017) NEJM 377(12): 1119-1131 (PMID: 28845751) • Canakinumab reduced rate of major cardiovascular events. But participants remained at risk of recurrent CV events. • Could efficacy be improved by targeting other elements of the IL-1β pathway? • What information does the GtoImmuPdb contain that could inform further research?
  28. 28. Potential mechanisms to modulate the IL-1b pathway 28 “There remains substantial residual inflammatory risk related to both IL-18 and IL-6 after IL-1β inhibition with canakinumab. These data support further pharmacologic development of therapies for atherothrombosis that target IL-18 or IL-6 signalling, or that can simultaneously inhibit both IL-1β and IL-18 (such as NLRP3 inflammasome inhibitors).” Ridker PM et al. (2019) European Heart Journal. doi: 10.1093/eurheartj/ehz542. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG
  29. 29. Potential mechanisms to modulate the IL-1b pathway 29 What can GtoImmuPdb tell us about: i. IL-6 ii. IL-18 iii. NLRP3 WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG
  30. 30. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 30 Interleukins list Links through to ligand summary page for IL-6
  31. 31. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 31 Searching for IL-6 Autocomplete for target, ligand and family names Results are ranked Results relevant to immunopharmacology are upweighted. Results can be downloaded as CSV
  32. 32. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 32 IL-6 ligand summary page Immunopharmacology tab Highlighting pro- and anti- inflammatory effects of IL-6 and role in treatment of Rheumatoid arthritis
  33. 33. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 33 IL-6 ligand summary page • Biological activity tab – list binding data for 4 ligands • 3 antibodies one of which, siltuximab is already an approved drug • A useful starting point when considering a way to target IL-6 – pharmacological data and immunological context.
  34. 34. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 34 IL-18 ligand summary page • Driver of macrophage activation syndrome (MAS) • Role of tadekinig alfa peptide in MAS
  35. 35. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 35 IL-18 ligand summary page Tadekinig alfa is a recombinant IL-18 binding protein that acts as a functional antagonist of IL-18 activity. It is a clinical lead (Ph3) for IL-18-driven MAS-like syndrome. Evidence indicates that this is a druggable target in the IL-1 pathway.
  36. 36. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 36 There is evidence of pharmacological modulation of NLRP3 in GtoImmuPdb, including evidence that one inhibitor, dapansutrile is a clinical lead for autoinflammatory disease and heart failure NLRP3 - Inhibitors
  37. 37. Case study summary 38 GtoImmuPdb contains curated evidence which supports the proposition that modulation of targets at different levels of the IL-1 pathway have anti- inflammatory outcomes These mechanisms could be helpful in developing novel approaches to reduce vascular inflammation in cardiovascular disease WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG
  38. 38. Overview • • • How to view immuno-relevant content • • • • • Disease Summary Pages • WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 39
  39. 39. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 40 Disease Summary Pages GtoPdb already has some data associated with diseases. More data associated with disease through GtoImmuPdb Developed disease summary pages to consolidate the data. Access via disease list – indicating targets and ligands associated with each disease
  40. 40. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 41 Disease Summary Pages - CLL • Associated targets/ligands • Synonyms • Links to external resources
  41. 41. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 42 Disease Summary Pages - CLL Targets section • Pathophysiology/mutation data • Curator comments • References • Key ligands interactions • 4 antibodies, 3 of which are approved drugs
  42. 42. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 43 Disease Summary Pages - CLL Ligands section • Expandable comments field • Rituximab – role in treating CD20- positive non-Hodgkins lymphoma and CLL • Also highlights role in several other auto-immune conditions and suppression of antibody-mediated organ rejection
  43. 43. Overview • • • How to view immuno-relevant content • • • • • • Advanced Search WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 44
  44. 44. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 45 Advanced Search: Targets Advanced Search Linked from menu-bar and gives access to more specific ways to search the database
  45. 45. 46WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG Advanced search: Targets UniProt ChEMBL Ensembl HGNC ID/symbol RefSeqs Entrez Gene ID Allows search on specific fields Includes immunopharmacology comments, processes, cell types and disease Via Reference BLAST tool
  46. 46. 47WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG Advanced search: Ligands BindingDB CAS registry number ChEBI ChEMBL ligand ID DrugBank IMGT/mAb-DB InChIs PDB IDs PubChem CID
  47. 47. 48WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG Advanced search: Pharmacology UniProt ChEMBL Ensembl HGNC ID/symbol MGI ID/symbol RGD ID/symbol RefSeqs Entrez Gene ID
  48. 48. 49WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG Advanced search: Pharmacology Advanced search results can be downloaded as CSV Pharmacology search lists interactions for each target
  49. 49. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 50 Web Services Computational access to the data in the database The web services currently serve up JSON files Users can retrieve families, targets, genes, ligands, interactions and text annotations.
  50. 50. 51WWW.GUIDETOPHARMACOLOGY.ORG Immunology paper submitted! Publications Email Twitter @GuidetoPHARM Blog
  51. 51. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 52 GtoImmuPdb is an open-access resource • Connecting pharmacological data to immunological concepts • Expanded to include associations with immunological processes, cell type and disease • New portal to prioritise access and display of immune data GtoImmuPdb can equips immunologists with a means to discover pharmacological agents useful in their research Provides a foundation for developing research into therapeutic modifiers of the immune system Conclusions
  52. 52. Acknowledgements WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 53 GtoImmuPdb Scientific Advisors Stephen P.H. Alexander, UK Stephen Anderton, UK Clare Bryant, UK Anthony P. Davenport, UK Jamie A. Davies, UK Christian Doerig, Australia Doriano Fabbro, Switzerland Francesca Levi-Schaffer, Israel Michael Spedding, France Database Development and Curation Simon D. Harding, Senior Database Developer, UK Elena Faccenda, Database Curator, UK Christopher Southan, Database Curator, UK Adam Pawson, Senior Database Curator, UK Dr. Joanna P. Sharman, Novo Nordisk, UK Thanks also to Expert subcommittees IUPHAR ImmuPhar Section Pasquale Maffia, University of Glasgow Adriano Rossi, University of Edinburgh Georgia Perona-Wright, University of Glasgow