pistoia alliance rsc evening event 2015: stefan klostermann, roche, on the helm antibody editor

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