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Advancing the state of antibody 3d modeling
How can we address the gap in the PDB?
A community discussion - September 22, 2015
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This webinar is being recorded
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Agenda
• Introduction Carmen Nitsche (Pistoia Alliance)• The need for more antibody
structures Charlotte Deane (University of Oxford)• Antibody structures in the protein data
bank Stephen Burley (PDB) • The Pharma challenge Sebastian Kelm (UCB),
Guy Georges (Roche), Bojana Popovic (Medimmune)
• Introduction to the D3R project Vicki Feher (UCSD)
• From idea to project Carmen Nitsche• Panel & audience discussion
September 22, 2015
The need for more antibody structuresPistoia alliance webinarProfessor Charlotte Deane (University of Oxford)
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Structural Antibody Databasehttp://opig.stats.ox.ac.uk/webapps/sabdab
Antibody Structures 2165
Structures with at least one paired VH/VL
1898
Number of Fv regions 4130
Structures with defined affinities 211
SAbDab Contents (15/09/2015)
J. Dunbar, K. Krawczyk, J. Leem, T. Baker, A. Fuchs, G. Georges, J. Shi, C.M. Deane, SAbDab: the Structural Antibody Database, NAR, 2014
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What’s the structural data for?Prediction
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What’s the structural data for?Prediction
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Why do we need more structures?
• What is the structural coverage we really have?– There are > 2000 paired antibody structures– Non-redundant in sequence at 99% only ~1000
• Why would more antibody structures help?– After all there are >100,000 structures in the PDB– Antibodies are different from other proteins– So if we want to improve our ability to model or
predict their binding we need more Antibody structures and complexes
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The Antibody Modelling Assessment – II(backbone RMSD)
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Numbers
• It has been estimated that humans generate about 10 billion different antibodies, each capable of binding a distinct epitope
• Compared to our 1000 non-redundant structures
• Its possible to model the framework to within 1A ~75% of the time if the template used has greater than 80% sequence identity.
• For CDRs the challenge is even greater10
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The structural coverage of antibody sequence space
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The rest of the PDB doesn’t help – CDR-H3
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The rest of the PDB doesn’t help – binding site residues• Antibodies
using different residues to bind than other proteins
• Statistical calculations improve with an increase in data
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The need for more antibody structures
• We only have a small sample currently ~1000 non redundant– Fail to accurately model even the framework for large
parts of the human antibody repertoire
• Antibodies are distinct from general proteins– Conformations CDR-H3– Residues use for binding
• More structures would improve our predictive power
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Antibody Structures in the Protein Data Bank
Stephen Burley (Rutgers)
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Antibody Structures in the Protein Data Bank
Stephen K. Burley, M.D., D.Phil.Director, Center for Integrative Proteomics Research
Director, RCSB Protein Data Bank
Founding Director, Institute for Quantitative Biomedicine
Distinguished Professor, Department of Chemistry and Chemical Biology
Member, Rutgers Cancer Institute of New Jersey
Rutgers, The State University of New Jersey
Outline About the PDB Archive and wwPDB Consortium Current Antibody Holdings in the PDB Challenges Ahead
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Outline About the PDB Archive and wwPDB Consortium Current Antibody Holdings in the PDB Challenges Ahead
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Protein Data Bank
First open access digital resource in all of biology (established in 1971 with 7 protein structures)
Single global archive of 3-D macromolecular structures (112,131 entries today!)
US PDB based at Rutgers/UCSD – Funded by NSF/NIH/DoE
Data, tools and resources freely available via www.rcsb.org
User Communities include – Structural Biologists (~25%) Scientists, Educators, Students, Patients, General Public
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Worldwide Protein Data Bank Consortium
Four Regional Data Centers RCSB PDB (Rutgers/UCSD) PDBj (Osaka University) PDBe (EMBL-EBI) BioMagResBank (UWisconsin)
Governing agreement ensures data are freely available
Formalized procedures for “Data In” validation, representation, and annotation
Each Data Center provides unique “Data Out” services for query, reporting, and analysis
a
wwpdb.org
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PDB Depositors>800 new entries/month
RCSB PDB347 million
PDBe100 million
PDBj58 million
PDB Users FTP and RSYNC Download Traffic in 2014:505 million downloads
Growing Number of
PDB Depositions
As of 2014, ~50% increase in the number of global depositions since 2008
Growing Global Reach
20002001
20022003
20042005
20062007
20082009
20102011
20122013
20142015
20162017
20180
2000
4000
6000
8000
10000
12000
14000Total Number of Annual DepositionsProjected Annual Depositions
Year
# o
f Ent
ries
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Outline About the PDB Archive and wwPDB Consortium Current Antibody Holdings in the PDB Challenges Ahead
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PDB Archive Antibody (Ab) Metrics
BLAST Search of PDB Archive revealed structures of >5000 Ig chains
6 major Ig sequence clusters corresponding to light (green&yellow) and heavy (blue&red)
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PDB Archive US FDA Approved Ab Metrics
US FDA has approved 42 monoclonal Abs
PDB Archive contains 19 7 Fab-only structures 6 Fab-antigen structures 6 Fab-only + Fab-antigen
structures
No public domain structures for 23 US FDA-approved monoclonal Abs
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PDB ID 1yy8Li et al. (2005) Cancer Cell 7, 301-311
cetuximab/Erbitux
PDB Archive US FDA Approved Ab Metrics
US FDA has approved 42 monoclonal Abs
PDB Archive contains 19 7 Fab-only structures 6 Fab-antigen structures 6 Fab-only + Fab-antigen
structures
No public domain structures for 23 US FDA-approved monoclonal Abs
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PDB ID 1yy9Li et al. (2005) Cancer Cell 7, 301-311
cetuximab/Erbitux+EGFR
PDB Archive Nanobodies
PDB Archive also contains interesting structures of some nanobody-antigen complexes
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cetuximab/Erbitux+Nanobody
PDB ID 4krpSchmitz et al. (2013) Structure 21 , 1214-1224
PDB Archive Nanobodies
PDB Archive also contains interesting structures of some nanobody-antigen complexes
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PDB ID 4krpSchmitz et al. (2013) Structure 21 , 1214-1224
cetuximab/Erbitux+Nanobody
Outline About the PDB Archive and wwPDB Consortium Current Antibody Holdings in the PDB Challenges Ahead
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Challenges Ahead
Access to Fabs of the remaining 23 US FDA approved monoclonal Abs
Access to other Fabs Access to antigens! Access to Fab-Antigen
structures in PharmaData Bases!
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PDB ID 1yy9Li et al. (2005) Cancer Cell 7, 301-311
cetuximab/Erbitux+EGFR
Acknowledgements
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The RCSB PDB is funded by a grant from the National Science Foundation, the National Institutes of Health, and the US Department of Energy.
Why do we need more Antibody structures?the pharma perspective
Sebastian Kelm (UCB), Guy Georges (Roche) , Bojana Popovic (Medimmune)
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Drug Design Data Resource (D3R)An open resource to advance computer aided drug design
Vicki Feher (UCSD)
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Drug Design Data Resource (D3R)An open resource to advance computer aided drug design
UCSD PIs: Rommie Amaro, Vicki Feher, Mike GilsonRutgers PI: Stephen Burley NIGMS U01 Awarded September 15, 2014
Aim 2 – Computer-Aided Drug Design Community Challenges & Workshops
Aim 1 - Collection of High Quality CADD Datasets from Pharmaceutical Companies
Aim 3 – Publicly Available Website with Database & Workflows
Specific Aims
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NIH Funded Mission
NIH PRIMARY GOAL: Provide previously unseen datasets for developers of protein-ligand docking programs and affinity scoring methods
Synergistic Goal with RCSB PDB: Public release of more industry crystal structures
Benefits to Pharma & Academe: More predictive drug discovery methods
Currently Working With:
• For Docking / Scoring Challenges (real systems)• CSAR/Abbvie – Hsp90 (up)• Genentech – Map4K4 (on deck)• Structural Genomics Consortium, Oxford & Toronto• GSK• Vertex• Roche• BMS• Academic groups
• For SAMPL5 Challenge (model systems)• Genentech, David Mobley, John Chodera• Lyle Isaacs, Bruce Gibb for Host-Guest
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Datasets
Blinded Prediction Challenges
• Annual Challenges – First one launched last week!!• Protein-ligand datasets• SAMPL small molecule data challenges• Teach-Discover-Treat (TDT)
• Continuous Evaluation of Ligand Protein Predictions (CELPP)• PDB early releases for automated docking servers
• Release of INCHI and protein sequence 5 days before structures
• Coordination with CAMEO/CASP• Early adopters and D3R implementation
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• First Workshop – March 9-12, 2016
• Forum for Challenge Result Discussions• Presentations by dataset donors• Presentations by challenge participants• “Best practices” discussions
• Promote CADD community interactions • Industry & academia• Dockers, SAMPL, TDT, CAMEO/CASP• Computational and Structural (PDB)
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Annual Workshop
Website and Database Capabilities
Our website: drugdesigndata.org Launched July 2015!
Web pages are under construction to handle:- Result uploads- Relational database interface to support queries- Workflow information, upload and distribution- Workshop information
Acquiring GPU cluster from U01 Equipment Supplement Opportunity – to be funded! Will help with CELPP and other community efforts
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SAB• Aled Edwards, SGC• Charles Grimshaw, Takeda Pharmaceuticals• Martha Head, GlaxoSmithKline• David Mobley, UC Irvine• John Moult, University of Maryland • Adrian Roitberg, University of Florida• Torsten Schwede, Biozentrum, University of Basel
Funding & Support• NIH U01• UCSD Center for Drug Discovery Innovation• UCSD Center for Research in Biological Systems
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UCSD• Michael Baitaluk• Mike Chiu• Symon Gathiaka• Jeff Grethe• Shuai Liu• Tiqing Liu• Burak Ozyurt• Rob Swift• Jane Yin
Rutgers• Huanwang Yang• Jasmine Young
U. Colorado Boulder• Mike Shirts
People and Support
September 22, 2015
From Idea to ProjectNext steps for the “Antibody structures in the PDB” idea
Carmen Nitsche (Pistoia Alliance)
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"Antibody Structures in the PDB" Webinar 41
Pistoia Alliance Mission
Lowering the barriers to innovation
in life science R&D
by improving inter-operability of business processes
through pre-competitive collaboration
22 September, 2015
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"Antibody Structures in the PDB" Webinar 42
Pistoia Alliance project process
22 September, 2015
• Business case compiled• Fundraising efforts begin• Steering committee
formed (funders)– Set the charter
• Project team established with champion, project lead, project manager +interested members– Execute on the charter– Can seek advice from
“expert community,” which can include non-members
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"Antibody Structures in the PDB" Webinar 43
Proposed deliverables and timelines
22 September, 2015
2016Q1 Q2 Q3
Phase 1 start
Solicit post-competitive antibody samples from member companies (coordinate the effort)
Survey community/review literature to identify highest value antibodies to crystallize and analyze in Phase 2
Begin writing proposal for Phase 2 funding
Report on first 6 months of Phase 1 post-competitive submissions
Draft requirements for post-competitive sample submission (work with SGC, etc)
Review and recommend from which granting agency to seek funding for Phase 2
Submit Phase 2 funding proposal
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"Antibody Structures in the PDB" Webinar 44
Estimated project costs
22 September, 2015
• Phase 1– Project management– Grant proposal preparation– Soliciting post-competitive sample depositions– 9 months estimated costs (includes PM, grant
writing consultant, BD, communications budget) ~$160K
• Phase 2– Work would be contracted, e.g. with the Structural
Genomics Consortium. Grant request will likely be in the $5M range (covering 100-200 structures)
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"Antibody Structures in the PDB" Webinar 4522 September, 2015
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"Antibody Structures in the PDB" Webinar 46
Stay up-to-date by checking IP3
22 September, 2015
https://main.qmarkets.org/live/pistoia/node/1480
Panel & audience discussion
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