View
373
Download
4
Category
Preview:
Citation preview
The HELM Antibody Editor
Stefan KlostermannRoche Innovation Center Penzberg
Pistoia Alliance Spring Conference,
Zürich, 14. April 2015
Agenda
• The motivation for
• The HELM Antibody Editor
• DEMO: From raw sequences to drugs
Classical chemistry
• Aspirin
• Acetylsalicylic acid
SMILES
O=C(Oc1ccccc1C(=O)O)C
InChI
1S/C9H8O4/c1-6(10)13-8-5-3-2-4-7(8)9(11)12/h2-5H,1H3,(H,11,12)
A more biological example
Conjugate of peptide and DNA oligo
• Peptide CHRISTIAN with Ser replaced by dSer
• linked via SMCC (bifunctional linker)
• to oligo CTAG
Classical chemical notationsFull molecular structure - SMILES
• [H]N[C@@H](CSC(=O)C1CCC(CN2C(=O)CC(OC[C@H]3O[C@@H]([C@H](O)[C@@H]3OP(O)(=O)OC[C@H]3O[C@@H]([C@H](O)[C@@H]3OP(O)(=O)OC[C@H]3O[C@@H]([C@H](O)[C@@H]3OP(O)(=O)OC[C@H]3O[C@@H]([C@H](O)[C@@H]3O[H])N3C=NC4=C3N=C(N)NC4=O)N3C=NC4=C3N=CN=C4N)N3C=C(C)C(=O)NC3=O)N3C=CC(N)=NC3=O)C2=O)CC1)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(O)=O
PEPTIDE1{C.H.R.I.[dS].T.I.A.N}|CHEM1{[SMCC]}|RNA1{R(C)P.R(T)P.R(A)P.R(G)}$RNA1,CHEM1,1:R1-1:R2|PEPTIDE1,CHEM1,1:R3-1:R1$$$
HELMNotation and editor views of given example
PEPTIDE1{C.H.R.I.[dS].T.I.A.N}|CHEM1{[SMCC]}|RNA1{R(C)P.R(T)P.R(A)P.R(G)}$RNA1,CHEM1,1:R1-1:R2|PEPTIDE1,CHEM1,1:R3-1:R1$$$
• Limited set of biological building blocks is packed into monomer library
• Notation supports homology searching (a least on natural analogues)
HELMBackground
• Hierarchical Editing Language for Macromolecules– Notation– HELM Editor & Toolkit
• Released by Pfizer to the for public distribution– http://openhelm.org/ Github
• Emerging new notation standard for complex biologicals
Agenda
• The motivation for
• The HELM Antibody Editor
• DEMO: From raw sequences to drugs
12 3
4
HELM for Antibodies
• Why antibodies? – Highly potent and specific drugs especially in Oncology / Immunology
• What makes antibodies a bit special?– Multiple peptide chains – Intra- + inter- chain Cys-Cys bonds– Added functional modules / payloads– Varying complex designs– Designed mutations
LCHC
LCHC
HELM Antibody Editorto 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 EditorDecomposition & Assembly
• Variable, hinge, constant
• V: germlines, C: isotypes
• Species ( human?)
• Mutations (knob-into-hole)
• Peptides, linkers, payloads
bispecific
trispecific
effector protein
knob-into-hole
Xmab
HELM Antibody EditorEnable Registration & Data Analysis
Enable registration
• Unique identifier (check)
• Full chemical structure
• Domains & annotations
• Antibody format (used modules)
• Antibody depiction
• Goal: Fully automatic even starting with raw sequences!
Data analysis
1) SAR analysis of
• Specificities
• Antibody formats
• Linker types/lengths
• Payloads (+position)
2) Retrieval of components
21
3
Agenda
• The motivation for
• The HELM Antibody Editor
• DEMO: From raw sequences to drugs
DEMONSTRATIONHELM Antibody Editor
HELMHELM Editor view of demoed complex antibody drug
Role of HELMfor the HELM Antibody Editor
• HELM Notation used for registration
PEPTIDE1{C.H.R.I.[dS].T.I.A.N}|CHEM1{[SMCC]}|RNA1{R(C)P.R(T)P.R(A)P.R(G)}$RNA1,CHEM1,1:R1-1:R2|PEPTIDE1,CHEM1,1:R3-1:R1$$$
• HELM Toolkit used for coding
• HELM Editor used for manipulations of domains (e.g. for ADCs)
Summary
The HELM Antibody Editor
• enables an easy (usually automatic) registration of even complex antibody formats
– for SAR analysis within and across projects– and full search & retrieval of all components.
• has been made public in the tradition of the HELM Editor and is availablenow at https://github.com/PistoiaHELM/HELMAntibodyEditor.
AcknowledgementsTo 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)
• Clemens Wrzodek (Roche pREDi, Penzberg)
Domain recognition (quattro research GmbH, Martinsried, GermanyBernhard Schirm, project lead)
• Anne Mund (Trainee)
• Marco Lanig
Doing now what patients need next
Recommended