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EUGM 2013 - Sergio H. Rotstein (Pfizer): What about the “big guys”? The emerging HELM standard for macromolecular representation and the Pistoia Alliance
 

EUGM 2013 - Sergio H. Rotstein (Pfizer): What about the “big guys”? The emerging HELM standard for macromolecular representation and the Pistoia Alliance

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The recent increase in utilization of complex macromolecules such as Antibody-Drug Conjugates (ADCs) as therapeutic agents has revealed a substantial gap in the biopharmaceutical industry’s ...

The recent increase in utilization of complex macromolecules such as Antibody-Drug Conjugates (ADCs) as therapeutic agents has revealed a substantial gap in the biopharmaceutical industry’s portfolio of informatics tools and methods, most of which were designed to work primarily with either small molecules or unmodified and unconjugated amino acid and nucleotide sequences. The Hierarchical Editing Language for Macromolecules (HELM), along with a software toolkit that leverages that language was developed by Pfizer researchers to address this gap (see J. Chem. Inf. Model 2012, 52, 2796-2806). HELM and related technologies such as SCSR (Self-Contained Sequence Representation, see: JChem Inf Model. 2011 51, 2186-208.), enable the representation of unnatural, conjugated or otherwise modified building blocks in biopolymers such as oligonucleotides, peptides, proteins and ADCs. HELM is being released into the Open Source and the Pistoia Alliance has initiated a project that has the goals of (1) facilitating this release, (2) adopting HELM as an industry standard for the manipulation and exchange of complex biomolecule data, and (3) setting up the organizational infrastructure to govern the future development of the standard. Given the recent FDA approval of the Antibody Drug Conjugate Kadcyla (Ado-Trastuzumab Emtansine) for Her2-Positive Metastatic Breast Cancer, one can reasonably assume that standards such as HELM and associated software tools will play an increasingly prominent role as part of the modern drug discovery informatics arsenal.

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    EUGM 2013 - Sergio H. Rotstein (Pfizer): What about the “big guys”? The emerging HELM standard for macromolecular representation and the Pistoia Alliance EUGM 2013 - Sergio H. Rotstein (Pfizer): What about the “big guys”? The emerging HELM standard for macromolecular representation and the Pistoia Alliance Presentation Transcript

    • What About the Big Guys?The emerging HELM standard for macromolecular representationand the Pistoia AllianceSergio H. Rotstein – Pfizer IncorporatedSergio.H.Rotstein@Pfizer.com
    • Introduction• Pfizer Goal: “Top-tier biotherapeutics company by 2015”–But informatics infrastructure was inadequate• Biomolecules Team Goal: Remediate infrastructure to enablebiomolecule–Registration–Visualization–Analysis and design–Workflows• Many companies facing a similar challenge• Pistoia HELM Goal: Facilitate the public release of HELM, providing astandard for data exchange and reducing need for other companies todevelop their own equivalent systems2
    • What is a “Biomolecule”?PeptidesTherapeuticProteinsADCsAntibodiesVaccinesASOssiRNAsFor our purposes, anythingthat is not a small molecule isa biomoleculeGoal• Eliminate biomoleculepenalty• Make these entities first-class citizens of theInformatics tool portfolio3
    • GAPSo what’s the problem?NNHOOONNHOOOSmallMoleculesSequencesBiomoleculesSmall Molecule Tools Sequence-Based Tools4
    • “Fit-for-Purpose” Structure RepresentationWe need to enable the representation,manipulation and visualization of eachmolecule type in a way that is appropriatefor its size and complexity5
    • Fit for Purpose: “Monomer” Level• While you could draw out an oligonucleotide like this:• The representation is likely more intuitive / practical:6
    • Fit for Purpose: Sequence Level• But even the monomer level representation would not scale well toproteins with hundreds of amino acids. Larger molecules require amore sequence-oriented representation:7
    • Fit for Purpose: Component Level• For multi-component structures such as antibody drug conjugates,component level representations are required to enable eachcomponent to dealt with separately.“Collapsed” AntibodyExpanded DrugAb8
    • Hierarchical Editing Language for Macromolecules9–Hierarchical – Amenable to the various “levels”• Complex Polymer ⇒ Simple Polymer ⇒ Monomer ⇒ Atom–Extensible• Allowing addition of new biopolymer types–(Reasonably) comprehensive• e.g. Allowing representation of oligonucleotide hybridization–Canonicalizable• Facilitating uniqueness checking–(Somewhat) human-readable
    • HELM Example: Simple polymer• HELM notation: A.R.G.[dF].C.K.[ahA].E.D.A–Non-natural amino acid codes are enclosed in squarebrackets• Natural equivalent: ARGFCKXEDA10
    • HELM Example: Complex Polymer11
    • Monomer Database• Each monomer used in the notation needs to be predefined in a monomerdatabase• The database includes the chemical structure of the monomer and a descriptionof all acceptable attachment points12
    • J. Chem. Inf. Model 2012, 52, 2796-280613
    • HELM at Pfizer: DrawingPME14
    • HELM at Pfizer: Registration15PMR
    • HELM at Pfizer: Analysis & Design16PFREDPFRED: A computational tool for siRNA and antisense design. Simon Xi, Qing Cao, ChristineLawrence, Tianhong Zhang, Simone Sciabola, Sergio Rotstein, Jason Hughes, Daniel Caffrey,and Robert Stanton, PLOS ONE, Submitted
    • http://pistoiaalliance.org @PistoiaAlliancePistoia Alliance HELM ProjectHierarchical Editing Language forMacromoleculesDomain Lead - Sergio RotsteinResearch Business Technology, PfizerSergio@PistoiaAlliance.org
    • HELM Project AimsObjective:Establish and promote HELM as a biomolecule representation standard that can:– Provide a mechanism for data exchange between companies– Reduce software development costs by minimizing the need for companies todevelop similar functionality18
    • HELM Project Participation• There are currently 24 organizations involved• Most of these companies have at least one person actively working in a subgroupProject team members(Abbott) InChi Trust PfizerAccelrys Lundbeck RocheACDLabs InfoSys RSCBMS Merck SanofiCDD NextMove software ScilligenceCertara NIH Thompson ReutersChemAxon Novartis UCBGSK Open BEL Unilever20
    • PfizerHELM Project Phase 1HELM notationPME (PfizerMacromoleculeeditor)PMR (PfizerMacromoleculeregistration tool)IndependenceOpen source(hosted, licenced and managed)HELM Toolkit HELM editorPaperManagedHELM DefinitionCommercialsystemsCommercialsystemsCompanysystemsWell known andregarded21
    • HELM Phase 1 Achievements• The Open Source repository infrastructure has been put in place– GitHub• The Open Source license terms have been defined and incorporated into thecode– MIT License• The Contributor License terms have been defined and customized for thePistoia Alliance– Apache• An initial governance structure has been defined to govern the evolution of thetechnology after the initial release• The source code has been “de-Pfizerized” and deposited into GitHub• ChemAxon has created an applet version of PME (now “HELM Editor”), enablinginstallation-free evaluation– A user guide developed, video tutorials underway• Accelrys has demoed prototype HELM reader and writer components inPipeline Pilot• A website, OpenHelm.org, has been developed to enable interested parties tolearn more about the project, get involved, make contributions, etc.• Numerous publicity opportunities have been planned and executed to raiseawareness about the project and encourage additional involvement andadoption22
    • What’s Next?• The hard work has been done• Now we must ensure that:– HELM continues its growth and evolution in the open source domain– HELM creates value for our industry through its adoption bybiopharmaceutical companies and support by software vendors andservice providers• Great strides with ChemAxon and AccelrysPhase 1• Make HELM publically availableReview• Agree high priority next stepsPhase 2• Accelerate adoption throughan appropriate supportinfrastructure and targetedHELM improvement activitiesWe are here23
    • AcknowledgementsOur team Members (Subteam leads)• Akos Papp (ChemAxon)• Alex Allardyce (ChemAxon)• Alex Drijver (ChemAxon)• Andrey Yerin (ACD labs)• Dana Vanderwall (BMS)• Ed Currie (InfoSys)• Edvard Buki (ChemAxon)• Hans de Bie (ACDLabs)• Ian Stott (Unilever)• Jerry Winter (Unilever)• Jinbo Lee (Scilligence)• John Smith (GSK)• John Wise (Pistoia)• Keith Taylor (Accelrys)• Kirti Jindal (InfoSys)• Matthias Nolte (BMS)• Michael Cui (GSK)• Mike Travers (CDD)• Rama Bhamidpati (GSK)• Roland Knispel (ChemAxon)• Roland Molnar (ChemAxon)• Sergio Rotstein (Pfizer)• Stefan Klostermann (Roche)• Ted Slater (OpenBEL)• Tianhong Zhang (Pfizer)• Tony Yuan (Scilligence)Our Steering Committee• John Wise (Pistoia Alliance)• Margret Assfalg (Roche)• Leah OBrien (GSK)• Ramesh Dervasula (BMS)• Christoph Brockel (Pfizer)• Alex Drijver (ChemAxon)Our Excellent Project Manager• Claire BellamySpecial thanks to ChemAxon for their generous contribution of software development resources!!24
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