Slides from a presentation given at the Pistoia Alliance European Conference 2015, in Zurich, Switzerland.

1. The HELM Antibody Editor
Stefan Klostermann
Roche Innovation Center Penzberg
Pistoia Alliance Spring Conference,
Zürich, 14. April 2015

2. Agenda
• The motivation for
• The HELM Antibody Editor
• DEMO: From raw sequences to drugs

3. 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)

4. 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

5. Classical chemical notations
Full molecular structure - SMILES
• [H]N[C@@H](CSC(=O)C1CCC(CN
2C(=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)NC
4=O)N3C=NC4=C3N=CN=C4N)N
3C=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

6. 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$$$
HELM
Notation and editor views of given example
PEPTIDE1{C.H.R.I.[dS].T.I.A.N}|CHEM1{[SMCC]}|RNA1{R(C)P.R(T)P.R(A)P.R(G)}
$RNA1,CHEM1,1:R1-1:R2|PEPTIDE1,CHEM1,1:R3-1:R1$$$
• Limited set of biological building blocks is packed into monomer library
• Notation supports homology searching (a least on natural analogues)

7. HELM
Background
• 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

8. Agenda
• The motivation for
• The HELM Antibody Editor
• DEMO: From raw sequences to drugs

9. 1
2 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
LC
HC
LC
HC

10. HELM Antibody Editor
to handle complex antibodies
• Analysis / decomposition
• Visualization
• Manipulation
• Registration

11. • 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
trispecific
effector protein
knob-into-hole
Xmab

12. HELM Antibody Editor
Enable 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
2
1
3

13. Agenda
• The motivation for
• The HELM Antibody Editor
• DEMO: From raw sequences to drugs

14. DEMONSTRATION
HELM Antibody Editor

15. HELM
HELM Editor view of demoed complex antibody drug

16. Role of HELM
for 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)

17. 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 available
now at https://github.com/PistoiaHELM/HELMAntibodyEditor.

18. 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)
• Clemens Wrzodek (Roche pREDi, Penzberg)
Domain recognition (quattro research GmbH, Martinsried, Germany
Bernhard Schirm, project lead)
• Anne Mund (Trainee)
• Marco Lanig

19. Doing now what patients need next