pistoia alliance rsc evening event 2015: stefan klostermann, roche, on the helm antibody editor
TRANSCRIPT
The HELM Antibody Editor
Stefan Klostermann, Roche pREDi
Agenda
• Scope of the HELM Antibody Editor
• DEMO: From raw sequences to drugs
• Role of
• DEMO: Integration with HELM Editor
HELM Antibody Editor
to handle complex antibodies
• Analysis / decomposition
• Visualization
• Manipulation
• Registration
• Detection, analysis and annotation of all domains
• Cys-Cys bonds
– Intra-domain (Ig-like)
– Inter-domains (scFv, scFab)
– Inter-chains (HC-HC/LC)
– Alert if free Cys left
HELM Antibody Editor
Decomposition & Assembly
• Variable, hinge, constant
• V: germlines, C: isotypes
• Species ( human?)
• Mutations (Knob into hole)
• Peptides, linkers, payloads
bispecific
trispecificeffector protein
knob into hole
Xmab
HELM Antibody EditorRegistration & Data Analysis
Registration
• Unique identifier (check)
• Full chemical structure
• Domains & annotations
• Antibody format (used modules)
• Antibody figure
• Fully automatic even startingwith just raw sequences!
Data analysis
1) SAR analysis of
• Specificities
• Antibody formats
• Linker types
• Payloads (+position)
2) Retrieval of components
21
3
HELM Antibody Editor
Open the HELM Editor
Note: Architecture of version
released soon will be different
HELM Antibody Editor
Start the HELM Antibody Editor
HELM Antibody Editor
Load raw sequences
HELM Antibody Editor
Raw sequences in FASTA format
HELM Antibody Editor
Review sequence decomposition
HELM Antibody Editor
Fully assembled and annotated
antibody drug molecule
HELM Antibody Editor
Review single domains
Role of HELM
Background
• Hierarchical Editing Language for Macromolecules
– Notation
– HELM Editor & toolkit
• Released by Pfizer to the Pistoia Alliance for public distribution
– http://openhelm.org/ Github
• Emerging new notation standard for complex biologicals
Role of HELM
for the HELM Antibody Editor
• HELM notation used for registration
• HELM toolkit used for coding
• HELM Editor used for manipulations of domains (e.g. for ADCs)
HELM Antibody Editor
Fully assembled and
annotated antibody
HELM Antibody Editor
Select a single domain for editing
HELM Editor
Edit domain in HELM Editor
HELM Editor
Load SMCC and connect to domain
HELM Editor
Load peptide and connect to SMCC
Sync back from HELM Editor
to HELM Antibody Editor
HELM Antibody Editor
Final drug molecule & further manipulations
Manually create Cys-Cys bonds
Manually delete Cys-Cys bonds
HELM Editor
Final drug molecule
Summary
The HELM Antibody Editor
• allows easy (usually automatic) registration of even complex antibody
formats
• ... to enable SAR analysis within and across projects
• ... and full search & retrieval of all components.
• Will be made public in the tradition of the HELM Editor
by Q1 2015 on Github.
Acknowledgements
To the developers
Domain editor and framework (Pharma Research and Early
Development Informatics, Roche Innovation Center Penzberg, Germany)
• Pandu Raharja (Trainee)
• Stefan Zilch (BridgingIT GmbH, Mannheim)
• Marco Lanig (quattro research GmbH, Martinsried)
Domain recognition (quattro research GmbH, Martinsried, Germany)
• Anne Mund (Trainee)
• Marco Lanig
Doing now what patients need next
HELM Antibody Editor
Methodology
• Chop chains into domains (use BLAST against domain library)
• Annotate domains
– e.g., Vh, Ck, linkers, peptides, effector proteins
– as defined by domain library
• Detect known mutations in constant domains
– e.g. LALA, knob-in-hole
– as defined by mutation table
• Detect known multi-domain modules
– e.g. XMab, scFv, scFab
– as defined by auto-connector rule set