1. Using the IUPHAR Guide to IMMUNOPHARMACOLOGY
Simon D. Harding
University of Edinburgh, UK
www.guidetoimmunopharmacology.org
15 DECEMBER
BPS PHARMACOLOGY 2019
1WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG

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. 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

4. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 4
Developing the Guide to IMMUNOPHARMACOLOGY
GtoP
Database
www.guidetopharmacology.org
IUPHAR/BPS Guide to
PHARMACOLOGY
(GtoPdb)
www.guidetoimmunopharmacology.org
IUPHAR/BPS Guide to
IMMUNOPHARMACOLOGY
(GtoImmuPdb)

5. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 5
Developing the Guide to IMMUNOPHARMACOLOGY
GtoP
Database
www.guidetoimmunopharmacology.org
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. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 6
Database content
www.guidetopharmacology.org/about.jsp
www.guidetoimmunopharmacology.org/immuno/immunoHelpPage.jsp#gtoimmupdb_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. Overview
•
•
• How to view immuno-relevant content
• Portal
• Target Data & Ligand Data
•
•
•
•
WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 7

8. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 8
Portal
Panels to browse
to target and
ligand lists by
category
Database search
Menu-bar

9. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 9
Target Data

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. 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. 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.

13. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 13
Ligand Data

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. 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. Overview
•
•
• How to view immuno-relevant content
•
•
• Target Data via immunological processes and cell types
•
•
•
WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 16

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. 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. 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. 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. 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. 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. 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. 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. 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. Overview
•
•
• How to view immuno-relevant content
•
•
•
• Accessing data on a case study on cardiovascular inflammation
•
•
WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 26

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. 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. 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. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 30
Interleukins list
Links through to
ligand summary
page for IL-6

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. 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. 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. 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. 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. 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. 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. Overview
•
•
• How to view immuno-relevant content
•
•
•
•
• Disease Summary Pages
•
WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 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. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 41
Disease Summary Pages - CLL
• Associated targets/ligands
• Synonyms
• Links to external resources

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. 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. Overview
•
•
• How to view immuno-relevant content
•
•
•
•
•
• Advanced Search
WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 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. 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. 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. 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. 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. 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.
https://www.guidetopharmacology.org/services/ligands?immuno=true

50. 51WWW.GUIDETOPHARMACOLOGY.ORG
Immunology paper
submitted!
Publications
Email enquiries@guidetopharmacology.org
Twitter @GuidetoPHARM
Blog https://blog.guidetopharmacology.org
www.guidetomalariapharmacology.org

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. 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