Pistoia Alliance European Conference 2015 - Stefan Klostermann / Roche

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


• 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




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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

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Agenda




DEMONSTRATIONHELM Antibody Editor

HELMHELM Editor view of demoed complex antibody drug

Role of HELMfor 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)

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

Science

Pistoia Alliance European Conference 2015 - Stefan Klostermann / Roche