SYMPOSIUM

IITM Perspectives Meeting: Biologics as Therapeutics19TH SEPTEMBER 2018, MSTC

2 | IITM Perspectives Meeting: Biologics as Therapeutics

WELCOME

Welcome to the first Perspectives meeting of the Wellcome Trust Infection Immunology and Translational Medicine (IITM) DTC. These meetings will be held every two years, and aim to provide state-of-the-art talks on topics relevant to the IITM course.

We start with the exciting area of the development of ‘Biologics as Therapeutics’. There has been an explosion of interest in harnessing the immune system and its components to treat infectious, autoimmune, and neoplastic conditions. The meeting brings together leaders from industry and academia who have been at the forefront of exploiting biologics, as well those who are involved in funding the development of novel therapeutics. We are extremely grateful to all the speakers for giving up their valuable time to participate in this inaugural Perspectives meeting, and look forward to a stimulating day.

Professor Christoph Tang Director of the IITM Programme

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PROGRAMME

9.00 Welcome & Session 1 Herman Waldmann, Mariagrazia Pizza

10.40 Coffeebreak

11.15 Session 2 GavinScreaton,ShaunCordoba

12.25 Open lunch (provided)

13.25 Session 3 RoundTableDiscussion StephenOakshott,SaraMarshall,BonnievanWilgenburg.Kerry Fisher

14.45 Coffeebreak

15.20 Session4 AusraRazanskiene,RichardPleass

16.30 Closingremarks

4 | IITM Perspectives Meeting: Biologics as Therapeutics

Professor Herman Waldmann PIattheSirWilliamDunnSchoolofPathology

Title of TalkReprogrammingoftheImmunesystem

SubjectThemAbCAMPATH-1Hwaslicensedforthetreatmentofrelapsing-remittingformsofmultiplesclerosisfouryearsago.Howeverworkonthisantibodybeganmorethanthreedecadesbefore,andstemmedfromfundamentalresearch on immune regulation and tolerance.

AhybridomawasisolatedthatproducedthemAb,CAMPATH-1,thatspecificallyrecognisestheglycoproteinCD52onhumanlymphocytes.SubsequentstudiesdemonstratedthatthemAbcouldfixhumancomplementandalsoeliminatelymphocytesinvitro.ThemAbwassuccessfullyengineeredforuseinhumans,andhasbeengiventopreventgraft-versus-host disease and transplant rejection, and toreversearangeofimmunedisorders.

Asidefromprovidinginsightsintotheregulationoftheimmunesystem,thedevelopmentandclinicaluseofCAMPATH-1havebeeninstructiveaboutthechallengesofturningscientificdiscoveriesintonoveltherapies.

BiographyHermanWaldmannisEmeritusProfessorofPathologyinOxford,recentlyretiredasHeadoftheSirWilliamDunnSchoolofPathology.Hismaininterestshavebeentoharnessthebody’sowntoleranceprocessestherapeuticallyforacceptanceoftransplantsandreversalofautoimmunediseases.Hislaboratorywasresponsibleforthe discovery and academic development oftheCAMPATH-1antibodiesculminatinginthelicensingofAlemtuzumab/Lemtrada.CurrentresearchfocusesonmechanismsbywhichregulatoryT-cellsmediatedominant(infectious)tolerance.HehasbeenaFellowoftheRoyalSocietysince1990,andwasafoundingFellowoftheAcademyofMedicalSciencesin1998.In2008,hewasawardedanHonoraryDoctoratefromtheUniversityofCambridge.

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Dr Mariagrazia Pizza SeniorScientificDirectorBacterialVaccines,GSKVaccines,Siena,Italy

Title of TalkNoveltechnologiesforthedevelopmentofnewtherapeuticvaccines

SubjectTechnologicalrevolutionshaveenabledthedevelopmentofnovelvaccinesandisexpectedtodelivervaccinesagainstotherinfectiousconditions,suchasantibiotic-resistantbacteria,chronicandrecurrentinfections.

Reverseandstructuralvaccinology,combinedwithsyntheticbiology,systemsbiology,andnoveladjuvants,arethebeginningofanewerain vaccinology. Additionally, the immune system cancontrolandeliminatechronicinfectionsand tumours so vaccination could, alone or incombinationwithimmunotherapy,elicitprotectiveimmuneresponses.Forexample,theimmunesystemcancureHIV,basedonpassiveimmunizationwithbroadlyneutralizingmonoclonalantibodies,whichrapidlyreduceviremiatoundetectablelevels.Thereforeresponsesinducedbyvaccination,couldhelpcurechronicallyinfectedpeople.

AnelegantexampleisprovidedbythenovelvaccineagainstHerpesZoster(HZ),whichcanrestore cell mediated and humoral immunity againstVaricellaZosterVirus(VZV).Thisvaccine,composedbytheVZVgEantigenwithAS01,anadjuvantthatboostscellularandhumoralresponses,has>90%efficacyinallagegroups.

BiographyMariagrazia Pizza received her degree in Chemistry andPharmaceuticalTechnologiesattheUniversityofNaples,Italy.FollowingaperiodattheEMBOlaboratoriesinHeidelberg,Germany,shemovedtoSiena,Italywhereshehasbeeneversinceleadingmanybacterialprojects.Shecontributedtothediscoveryofapertussisvaccinebasedonageneticallydetoxifiedtoxin,andtothediscoveryofanewvaccineagainstMeningococcusB,licensedinmanycountriesworldwide.MariagraziaiscurrentlySeniorScientificDirectorforBacterialVaccinesatGSKVaccines,inSiena.ShehasreceivedmanyscientificawardsandisanelectedmemberofEMBO,theEuropeanAcademyofMicrobiology,FellowoftheAmericanAcademyofMicrobiologyandVicePresidentofIUMS(InternationalUnionofMicrobiologySocieties).MariagraziaisalsoHonoraryVisitingProfessorattheUniversityofLeicester.Shehasover190publicationsininternationalpeer-reviewedjournalsandisco-inventorofmanypatents.

6 | IITM Perspectives Meeting: Biologics as Therapeutics

SubjectDengueisamosquitoborneviralinfectionoccurringintropicalandsubtropicalcountries.Thereareestimatedtobearound400millioninfectionsannually.Themajorityoftheseareself-limiting,but1-5%ofinfectionsleadtodenguehaemorrhagicfever,characterizedbyvascularleak,andinextremecasesshockandhaemorrhage.Dengueexistsasfourhighlydivergentserotypes;infectionwithoneserotypedoesnotprovideprotection against the other three. Interestingly, severe disease is much more common in secondaryasopposedtoprimaryinfections,implyingaroleoftheacquiredimmunesystemindiseasepathogenesis.Understandingimmuneenhancementiscrucialfordesigningsafe,effectivevaccines.ThroughcollaborationsinThailandandVietnamwehavebeendetailingimmuneresponsestodengueinchildren.IwilldescribeantibodyresponsestothesurfaceglycoproteinsprMandE,andtheEdimerepitope(EDE),anovelsitebridgingthe90dimersmakingupthevirionsurfaceandalsocrossreactsagainstZikavirus.

Professor Gavin Screaton HeadofMedicalSciences Division,OxfordUniversity

Title of TalkThehumanantibodyresponseindengueandZikavirusinection

BiographyProfessorScreatonreceivedhisfirstdegreefromCambridgein1984beforemovingtoOxfordtocomplete his medical studies in 1987. He then completed training in general internal medicine andobtainedaDPhilfromOxfordUniversityin1998.In2004,ProfessorScreatonwasappointedtotheChairofMedicineatImperialCollege.HereturnedtoOxfordasHeadoftheMedicalSciencesDivisioninOctober2017.

Hisresearch,whichhasbeensupportedbyaseriesofFellowshipsawardedbytheMRCandWellcomeTrust,hascoveredavarietyoftopicsfromcontrolofRNAprocessingandapoptosistoimmunology.ThecurrentinterestsofhislaboratoryrevolvearoundtheimmunologyofinfectiousdiseaseswithaspecialinterestindenguehaemorrhagicfeverandZika,wherehisresearchiscurrentlyfundedbytheWellcomeTrust,withactiveresearchcollaborationsinSouth-EastAsia.

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Dr Shaun Cordoba DirectorofSyntheticBiologyatAutolusTherapeutics

Title of TalkImmunotherapy:EngineeringTcellsforthetreatment

SubjectTherehavebeendramaticrecentadvancesinimmunotherapy,byengineeringTcellsforthetreatmentofcancer.Iwilloutlinecurrentstrategies, and latest immunotherapeutic approaches,andhighlightpre-clinicaldatausing a Chimeric Antigen Receptor.

BiographyIamcurrentlytheDirectorofSyntheticBiologyatAutolusTherapeuticswhereIdevelopChimericAntigenReceptors(CARs)forthetreatmentofcancers.IdidmyPhDattheUniversityofSydney,examininggeneexpressionprofilesinimmunecellsfrompatientsundergoingtransplantation.Ihaveheldpost-doctoralappointmentsattheUniversityofOxfordandImperialCollegeLondononTcellandNKcellactivation.

Bonnie van Wilgenburg Analyst,lifescienceventurecapitalfirmForbion

BiographyBonnievanWilgenburgisananalystatForbion,aleadingventurecapitalfirmthatworkscloselywithscientistsandentrepreneurstobuildlifesciencescompanies.Bonnie’sworkinvolvessourcingnewinvestment opportunities, evaluatingbusinessplans,completing venture transactions andcontributingtoportfoliomanagement. Previously she workedasanacademicscientistpublishingsixfirst-authorpapersinthefieldsofimmunology,stemcell research and virology. As a Marie-CuriefellowandrecipientoftheRoyalSocietytravelgrantsheinvestigatedtheroleofinnateT-cellsinresponsetoviralinfectionsinthelaboratoriesofProf.Klenerman(UniversityofOxford)andProf.McCluskey(UniversityofMelbourne).

BiographySara joined Wellcome in 2016 as HeadofClinicalandPhysiologicalSciences.SheobtainedhermedicaldegreefromtheNationalUniversityofIreland,andworkedasajuniordoctorinDublinbeforegoingtoStanfordUniversity,CaliforniaasfellowinLungTransplantation. She held an MRCClinicianScientistawardattheUniversityofOxford,andwasthenaClinicalSeniorLectureratImperialCollegewhereherresearchinterestsfocusedonthegeneticsoftransplantationandinflammatorydiseases.Prior to joining Wellcome, shewasProfessorofClinicalImmunologyattheUniversityofDundee,whereshewasalsoDirectoroftheDundeeClinicalAcademicTrackandDeputyHeadofR&DforNHSTayside.

Professor Sara Marshall HeadofClinicalandPhysiologicalSciences, Wellcome Trust

Round Table

BiographySteveistheHeadofInnovativeTechnologies at the Medical ResearchCouncil(MRC),partofUKResearchandInnovation.His role at the MRC involves oversightofseveraloftheMRC’stranslationalresearchand industry liaison schemes andactivities,alongsideworkwithotherfundersonmajorgovernmentinitiativesliketheIndustrial Strategy Challenge Fund.Afterundergraduateand postgraduate studies at theUniversityofCambridge,StevemovedtoNewYork,initiallyasapost-doctoralresearcheratBrooklynCollege,CUNYandsubsequentlyasascientist at PsychoGenics, a preclinical research company.

Steve Oakeshott Medical Research Council (MRC)

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Dr Kerry Fisher ChiefScientificOfficeratPsiOxusTherapeuticsandLecturer,OxfordUniversity

Title of TalkHarnessingoncolyticvirusesfortherapy

SubjectTranslatingcomplexbiologicaldrugcandidatesfromthelaboratorytoaclinicaltrialcanbechallenging.Thisisparticularlythecasefordeveloping oncolytic viruses as therapeutics, especiallywhenspeciesspecificityaffectsviralreplication and delivery, limiting the relevance ofanimalmodels.Thereisintenseinterestinunderstandinghowadministrationofoncolyticvirusescanbeintegratedintoourknowledgeoftumourimmunologyandheterogeneityto optimise therapeutic approaches.

BiographyKerryFisherhasbeenworkinginthefieldofoncolyticvirusesforover15yearsandisafoundingscientistofPsiOxusTherapeuticsandpreviouslyHybridSystems.HewasawardedaPhDintherapeuticgenedeliveryfromtheUniversityofBirminghamandhasspecializedinthesystemicadministrationofvirusesforthetreatmentofcancer. Heisparticularlyinterestedinhowvirusesreplicate,spreadandstimulateimmunecellswithinthetumourmicroenvironment.Kerry holds a research lectureship at the UniversityofOxfordandhaspublishedover60publicationsinthefieldofoncolyticvirusesandfiledover20patentapplications.

10 | IITM Perspectives Meeting: Biologics as Therapeutics

Dr Ausra Razanskiene ScientificManageratNomadsinVilnius,Lithuania

Title of TalkPlant-ExpressedAntimicrobialProteins

SubjectAntibioticshavebeencriticalincuringinfections;however,widespreaduseofantibioticshascausedtheemergenceantibiotic-resistantstrains.Withfewnewantibioticsinthepipeline,antibioticresistanceisaseriousglobalthreattopublichealth.

Plant-expressedcolicins,bacteriocinsnaturallyproducedbyE. coli thatkillorinhibitthegrowthofother E. coli strains,canbeeffectiveantibacterials.Colicin-likeproteinsfromKlebsiella(klebicins)and Pseudomonas aeruginosa (pyocins) can alsobeproducedinplants.Pyocinsexcellentlycontrol Pseudomonas pathovars in animal models.Therefore,colicin-likemoleculesareapromisingclassofantibacterials.Endolysinsarehydrolyticenzymesproducedbybacteriophagesduringthelyticphaseoftheirlifecycle,andhavebeenefficientlyexpressedinplants,withsomeproductsinclinicaltrialsandonthemarket.

Commercializationofbacteriocinsandendolysinscouldgenerateapipelineofnovelalternativestoantibiotics.Attractivecandidatescouldbeedibleand/ortopicalandrequireonlypartialpurification.

Biography1988-1992–biologystudiesinVilniusUniversity.

1992-1993-DEA(DiplomedesEtudesApprofondies)inPlantdevelopmentbiologyinParisVI(PierreetMarieCurie)University.

1993-1998-PhDstudiesinParisVIinPlantdevelopmentbiology,incollaborationwithInstitutdesSciencesVegetales(Gif-sur-Yvette),CNRS.

Since1998–scientist,laterseniorscientistinInstituteofBiotechnologyinVilnius(currentlyInstituteofBiotechnology,LifeScienceCenter,VilniusUniversity).Maininterest:recombinantexpressionofvirussurfaceandnucleocapsidproteins in yeast and plants and their applicationsfordiagnosticandvaccines.

Since2010–manageratUABNomads(daughtercompanyofNomadBioscienceGmbH).Thecompanyspecializesinplanttransientexpressionsystems.Wearecurrentlyfocussingonproductionofantimicrobialproteins,bacteriophagelysinsandbacteriocins.

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Professor Richard Pleass ProfessorofParasitology,LiverpoolSchoolofTropicalMedicine

Title of TalkN-terminalhingeglycosylationfornovelreceptor interactionsofIgGFcmonomersandmultimers

SubjectInneurology,intravenousimmunoglobulin(IVIG)servesasamainstaytherapyinimmune-mediatedneuropathies,includingchronicinflammatorypolyneuropathy(CIDP)andGuillain-Barresyndrome.

TheworldwideconsumptionofIVIGhasincreasedover300foldsince1980andcurrently~100tonsareconsumedperannum.SuppliesofIVIGwithintheNHSandgloballyarecriticallylimited,meaningthatpatientswithanurgentneedforthedrugareroutinelydeprivedofit.Therearesignificantclinicallimitationsresultingfromitsdependenceonhumandonorsformanufacture,andfromthefactthat<5%ofinjectedIVIG(correctlyglycosylated Fc) is therapeutically active, leading toarequirementforhighdoses(2g/kg)whenusedtotreatinflammatoryconditions,includingCIDP.Consequently,IVIGisexpensiveandadverseeventsduetoexcessiveproteinloadingarenotuncommon.ThechallengesassociatedwithmanufacturingandapplicationofIVIGrepresentanincentivetodevelopmoleculeswithimprovedefficacy,thesubjectofthepresentation.

BiographyAspartofmyWellcomeTrustfellowshipIdevelopedthefirstfullyhumanantibodiestargeting the malaria parasite, and have experienceingeneratingantibody-basedstructuresfornewapplications.

Ourrecentresearchhasfocussedoncreatingmultimericantibody-Fcplatformsforthedevelopmentofnewdrugsandvaccines.

ThistechnologywasrecognisedbytheawardoftheUniversalBiotechInnovationprizein2013andwasshortlistedfortheBionowProjectoftheYearin2014.

Despitetheseexcitingdevelopments,muchbasicsciencehasyettobeperformedtotakethesemoleculesintolessexploredareas.

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About IITM Programme

TheIITMDPhilprogrammeisfundedbytheWellcomeTrust and gives students the opportunity to complete three3-monthlaboratory-basedresearchprojectsindifferentlabsacrosstheuniversityduringtheirfirstyear.Attheendofthefirstyear,studentsthenchooseoneormoreoftheselabsinwhichtocompletetheirDPhilthesisprojectfortheremainingthreeyears.

TheprogrammeisdirectedbyProfessorChristophTang(Director)andProfessorHelenMcShane(Co-director).

Acknowledgements

TheIITMSymposiumisgenerouslysupportedbytheWellcomeTrust.ManythankstoDawnGibbons(theIITMcourseadministrator)fororganisingtoday’smeeting.