Table Of ContentPrinciples of Translational Science in Medicine
From Bench to Bedside
Principles of Translational Science
in Medicine
From Bench to Bedside
Third Edition
Edited by
Martin Wehling
Clinical Pharmacology Mannheim, University of Heidelberg,
Mannheim, Germany
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Contents
Part II
Listofcontributors xiii
Target identification and validation
Part I
Introduction 3. “Omics” translation: a challenge for
laboratory medicine 21
1. Introduction and definitions 3
MarioPlebani
MartinWehling Introduction 21
“Omics”:whatdoesitmean? 21
Whatistranslationalmedicine? 3
Proteomicsasaparadigmofproblemsin
Primarytranslationversussecondary
translationalmedicine 22
translation 4
Developmentofbiomarkers:fromdiscovery
Thehistoryoftranslationalmedicine,
toclinicalapplication 24
obstacles,andremits 5
Discovery 24
References 7
Identification/characterization 25
Validation 25
Standardization/harmonization 25
2. Problems, challenges, and initiatives in
Clinicalassociationandclinicalbenefit 27
translation 9 Translatingomicsintoclinicalpractice 27
Continuumoftranslationresearchandomics 29
MartinWehling
Conclusions 30
References 30
Attrition 9
Whattranslationalmedicinecanand
cannotdo 11 4. The power of genomics, metabolomics,
Thepresentstatusoftranslational
and other omics for target identification
medicine(initiativesand
and validation 33
deficiencies) 13
Newpathwaystodiscovery 13
DavidM.PereiraandJoa˜oC.Fernandes
Researchteamsofthefuture 13
Reengineeringtheclinicalresearch Introduction 33
enterprise 13 Genomics 33
Translationalscienceinmedicine: Genomictools 34
thecurrentchallenge 16 Applicationsofgenomicsinmolecular
References 17 medicine 40
v
vi Contents
Metabolomics 41 Malignantdiseases 77
Metabolomicsormetabonomics? 41 Translationalpharmacogeneticsandthe
Analyticaltechniquesinmetabolomics/ needforclinicalstudiestosupport
pharmacogeneticallydrivenprescribing 79
metabonomics 42
References 80
Omicsandbiomarkers 44
Metabolomicsandmetabonomicsinclinical
use 44 7. Tissue biobanks 85
Conclusion 45
References 45 LaraPlanas-PazandChantalPauli
Introduction 85
5. Potency analysis of cellular therapies: Theconceptofbiobanking 86
the role of molecular assays 49 Population-orientedbiobanks 86
Disease-orientedbiobanks 86
DavidF.Stroncek,PingJin,LipeiShao, Virtualbiobanks 86
EnaWang,JiaqiangRen,LucianoCastiello, Biobankingforresearch 87
MariannaSabatinoandFrancescoM.Marincola
Biobankingforclinicaluse 87
Typesofbiospecimens 87
Introduction 49
Potencytesting 51 Tissue 87
Complexitiesassociatedwithpotency Bodyfluids 88
testingofcellulartherapies 51 Cellularmodels 88
Factorsaffectingthepotencyofcellular Nucleicacids:DNAandRNA 89
therapies 52 Proteinandothersubcellularcomponents 89
Measuringpotencyofcellulartherapies 52 Qualityassuranceofbiospecimens 90
Geneexpressionarraysforpotencytesting 53 Biobankingintheeraofprecisionmedicine 90
Potentialapplicationsofgeneexpression Ethicalissues 90
profilingforpotencytesting 54 References 91
Predictingtheconfluenceofhuman
embryonickidney293cells 54
8. Animal models: value and
Celldifferentiationstatusanalysisof
translational potency 95
embryonicstemcells 55
Potencytestingofhematopoieticstemcells 55
PhilippMergenthalerandAndreasMeisel
Potencytestingofdendriticcells 56
CulturedCD41cells 60 Whatisthevalueofanimalmodels?
Pathophysiologicalconcepts 95
Bonemarrowstromalcell 60
Whatisagoodanimalmodelfor
CARTcells 62
translationalresearch? 96
MicroRNAsaspotencyassays 63
Modelingcomorbidities 96
Conclusions 63
References 64 Modelingcareofpatients 96
Whatisthetranslationalvalueofanimal
models? 97
Remediesforfailedtranslation:improving
6. Translational pharmacogenetics:
preclinicalresearch 99
pharmacogenetically driven clinical
Improvingmodels 99
decision making 71
Improverigorofpreclinicalstudies 100
Summary 101
JuliaCarolinStingl
References 101
Introduction 71
Pharmacogeneticsasatoolforimproving
9. Biomarkers in the context of
individualdrugtherapy 71
Typesofdrugtherapiesthatmightprofitfrom health authorities and consortia 105
pharmacogeneticdiagnostics 72
FrankDieterle
Thestatusoftranslationalpharmacogeneticsin
variousdrugtherapyfields 73 Introduction 105
Depression 73 Frombiomarkerstodiagnosticteststo
Cardiovasculardisease 73 improvepatientcare 105
Paintreatment 77 Invitrodiagnostictests 106
Contents vii
InvitrodiagnostictestsandUSregulations 106 Developmentofbiomarkers 154
InvitrodiagnostictestsandEurope Predictivityclassificationofbiomarkers
regulations 107 andscores 158
Companiondiagnostics 107 Casestudies 161
Labtests(CLIAtestorlab-developedtest) 109 References 163
Drugdevelopmenttools 109
Thecriticalpathinitiative 109
13. Genetics, molecular biomarkers,
Newregulatorypathwaysforqualification
and artificial intelligence to improve
ofbiomarkersanddrugdevelopment
diagnostic and prognostic efficacy 167
tools 110
Examples 110 AndreaPadoan,DaniaBozzatoand
Collaborationsforbiomarkersanddrug MarioPlebani
developmenttools 110
Public-privatepartnerships(cooperativeR&D Introduction 167
Sourceoferrorsinclinicalproteomics
agreements) 110
studies 168
Consortia 111
Sourceoferrorsinnext-generation
References 113
sequencing 168
Bioinformaticsandcomputationaltools
10. Human studies as a source of forclinicalproteomicstudies 169
target information 115 Bioinformaticsandcomputationaltools
fornext-generationsequencing 169
MartinWehling Artificialintelligence,machinelearning,
anddeeplearningtechniquestoimprove
Usingolddrugsfornewpurposes:baclofen 115
theclinicalutilityofclinicalproteomics
Serendipity:sildenafil 118
andgenetics 169
Reversepharmacology 118
References 121 Machinelearning:supervisedand
unsupervisedlearning 170
Techniquestoavoidoverfittingissues 170
11. Target profiling in terms of
Examplesoftheapplicationsofgenetics
translatability and early translation andmolecularmarkersfordiagnosticor
planning 123 prognosticpurposes 171
Ovariancancer 171
MartinWehling
Prostatecancer 172
Essentialdimensionsofearlytranslational Pancreaticcancer 174
assessment 124 Conclusions 174
Atranslatabilityscoringinstrument: References 174
riskbalancingofportfoliosandproject
improvement 126
14. Cardiovascular translational
Casestudies:applyingthetranslatability
biomarkers: translational aspects
scoringinstrumenttoreal-life
experiences 129 of hypertension, atherosclerosis,
References 132 and heart failure in drug
development in the digital era 177
Part III GeorgesvonDegenfeldandHubertTruebel
Biomarkers as key elements of Whatisnew? 177
Hypertension 178
successful translation
Introduction 178
Animalmodelsofhypertension 179
12. Biomarkers 135 Biomarkersofhypertension 180
Blood-bornebiomarkers 180
MartinWehling
Endothelialdysfunction 181
Definingbiomarkersasveryimportant Digitalbiomarkersofhypertension 181
contributorstotranslationalscience 135 Atherosclerosis 182
Classesofbiomarkers 138 Introduction 182
viii Contents
Animalmodelsofatherosclerosis 182 Workingmemory 210
Biomarkersforatherosclerosis 183 Selectiveattention 211
Imaging(digital)biomarkersin Imagingofgeneticsusceptibilityfactors 211
atherosclerosisconditions 183 Characterizationofantipsychoticdrug
Continuouslymeasureddigitalbiomarkers effects 214
inatherosclerosisconditions 183 Multiomicsandtransdiagnosticbiomarker
Heartfailure 184 discovery 215
Introduction 184 Conclusionsandfuturedirections 215
Animalmodelsinheartfailure 185 References 216
Valvularlesions 185
Dilatedcardiomyopathies 185 Part IV
Geneticallydrivenheartfailuremodels 185
Ischemicheartfailuremodels 185 Early clinical trial design
Traditionalbiomarkersofheartfailure 185
Solublemarkersforcardiacremodeling
17. Methodological studies 227
andfibrosis 186
Solublemarkersformyocardialstretch 186 FaisalAzam,RachelPhillips,RhianaNewport,
Markersofinflammation 187 RebeccaJohnson,RachelMidgleyand
Digitalbiomarkersofheartfailure 187 DavidJ.Kerr
CVbiomarkers:QuoVadis? 187
Casestudy:atrialfibrillation 188 ConventionalphaseItrialmethodology 227
Conclusion 189 Aims 227
References 189 Design 227
Patiententrycriteria 228
Specialdrugadministrationorprocedures 228
Patientconsent 229
15. Biomarkers in oncology 195
Calculationofthestartingdose 229
ValentinosKounnis,JonCleland,FaisalAzam, Doseescalation 229
RachelMidgleyandDavidJ.Kerr Numberofpatientsrequiredfordose
administration 229
Circulatingbiomarkers 196
Stoppingrules 230
Pharmacodynamicmarkers:
Measuringendpoints 230
targetinhibition 197
Focusonlungcancer 199 Toxicity 230
ThePD-1/PD-L1axis 200 Pharmacodynamicendpoints 230
Conclusion 201 Mechanism-orientedtrialdesign 231
References 201 Proof-of-mechanism 231
Proof-of-principle 231
Proof-of-concept 231
Canwemakego-or-no-godecisionsat
16. Translational medicine in psychiatry:
theendofphaseI? 232
challenges and imaging PhaseIItrials 232
biomarkers 203 Personalizedmedicine 232
Thecontributionofmodernimagingto
AndreasMeyer-Lindenberg,HeikeTostand early-phasetrials 233
EmanuelSchwarz Anatomicalandmolecularimaging
evaluation 233
Biologicaltreatmentofpsychiatricdisorders 203
Metabolicmeasurementsusingpositron
Specificchallengesoftranslationin
emissiontomographyligands 234
psychiatry 204
Choiceofimagingmodality 234
Unknownpathophysiology 204
Radiomics 234
Stigmaandthesecondtranslation 205
Quantificationimagingmethods 234
Newbiomarkersfortranslationinpsychiatry 205
TheroleofimaginginphaseItrials 234
Imagingbiomarkersinschizophrenia 206
Challengesfornovelimagingmethodologies
Structuralbrainbiomarkers 206 andclinicaltrials 235
Functionalimagingmarkersinschizophrenia 208 Conclusion 235
Auditoryandlanguageprocessing 209 Openaccessclinicaltrials 235
Motorfunctioning 209 References 235
Contents ix
Part V
18. The pharmaceutical research and
development productivity crisis: Toxicology in translation
can exploratory clinical studies be
of any help? 239
22. Pharmaceutical toxicology 265
SacodeVisserandHubertTruebel
SteffenW.Ernst,RichardKnight,
Traditionaldrugdevelopment 239 JennyRoyleandLauraStephenson
Definitionofexploratoryclinicalstudies 239
Introduction 265
Decisionmaking:regulatoryperspective
Discoverytoxicology 266
versuscompanyinternalperspectivein
Target 266
phaseIandphaseIIa 240
Chemistry 269
Theproblemathand:attritionversus
Patient 271
opportunityfocus 240
Regulatorytoxicology 271
Fromphasethinkingtoquestion-based
development 240 Historicalcontext 272
Doesthebiologicallyactivecompound Goodlaboratorypractice 273
oractivemetabolitesgettothesiteof Thegoalsofregulatorytoxicology 274
action? 240 Dose-responserelationships 275
Doesthecompoundcauseitsintended Translationalconsiderationsandcontext 275
pharmacological/functionaleffect(s)? 241 Animalmodelsandfutureperspectives 276
Doesthecompoundhavebeneficialeffects Alternativeapproachesinregulatory
onthediseaseoritspathophysiology? 241 toxicology:theexploratoryinvestigational
Whatisthetherapeuticwindowofthenew newdrugapproach 277
drug? 241 Biomarkers 278
Howdothesourcesofvariabilityindrug Preclinicalsafetyfromatranslational
responseinthetargetpopulationaffect perspective 278
References 278
thedevelopmentoftheproduct? 241
Highriskandvariablecosts:howto
23. Translational safety medicine 281
addresstherisk-costcombinationin
development? 241
SteffenW.Ernst,RichardKnight,
Realoptionsintranslationaldevelopment 242
JennyRoyleandLauraStephenson
Exploratorystudies:thescornperspective 242
Exploratorystudies:thevalueperspective 244 Introduction 281
Summary:challengesandoutlook 244 Stateofaffairsoftranslationalsafety
References 245 medicine 283
Constraintstoeffectivetranslationalsafety
medicine 286
19. Adaptive trial design 247 Thebrokensafetyvaluechain 286
Theconceptualapproachtosafety 286
MartinWehling Thenatureofsafetywork 288
Organizationalstructure 289
References 250
Practicingtranslationalsafetymedicine 289
Organizationalsetup 289
Insummary 298
20. Combining regulatory and
Translationalsafetyfuture 299
exploratory trials 251
References 302
MartinWehling
Part VI
References 255
Special topics in translation
21. Accelerating proof of concept 24. Cancer vaccines: translational
by smart early clinical trials 257 strategies 307
MartinWehling HoyoungM.MaengandJayA.Berzofsky
References 260 Introduction 307
x Contents
Historicperspectiveofimmunesystem Antibody-drugconjugates 335
involvementinthebiologyofcancer 307 Mechanismofactionofantibody-drug
Spontaneousregression 307 conjugates 337
Abscopalresponse 308 Antibody-drugconjugatesinpreclinical
Microbes:thefirstcancervaccine developmentandclinicaluse 337
platforminthehistoryofmodern
Choiceofantibody 340
medicine 309
Choiceoflinker 342
Discoveryofcytokinesandthefirstusage
Choiceofcytotoxicpayload 343
incancertreatment 310
Challengesinantibody-drugconjugate
Discoveryofwhitebloodcellsubtypesand
design,evaluationandtranslation 345
translationfrombenchtobed 310
Nucleicacid(cid:1)basedcancervaccines 312 Conclusion 345
Acknowledgments 346
Syntheticpeptidesasacancervaccine 314
References 346
Medicaladvanceswithmonoclonal
antibodiesinclinicalfields 315
Virus-basedcancervaccineplatforms 315 26. Orphan drugs: why is translation
Neoepitopevaccines 316
so successful? 351
Combinationstrategies 317
Cancervaccineswithbroadergoals 317 MartinWehling
Vaccinestargetingthetumor
Introduction 351
microenvironment 317
Specialcharacteristicsoftranslational
Vaccineswithpreventiveoradjuvant
processesfororphandrugs 352
purposes 318
References 355
Challengesandfuturedirections 318
Conclusion 319
References 319 Part VII
Biostatistics and modelling
25. Translational aspects of biologicals:
27. Translational science biostatistics 359
monoclonal antibodies and
GeorgFerberandEkkehardGlimm
antibody-drug conjugates as
examples 329 Statisticalproblemsintranslationalscience 359
Statisticalmodelsandstatisticalinference 360
SophiaN.Karagiannis,RicardaM.Hoffmann, Designandinterpretationofanexperiment 362
ManoNakamura,SilviaCrescioli, Multiplicity 365
HeatherJ.Bax,AliciaChenoweth, Biomarkers 366
AnthonyCheung,SophiaTsoka, Biologicalmodeling 368
JamesF.Spicer,KatieE.Lacyand
Example1:pharmacodynamics 368
DavidE.Thurston
Example2:pharmacokinetics 369
Overviewofmonoclonalantibodies Statisticalmodels 371
forcancertherapy 329 References 371
Structureandfunctionsofantibodies 330
Generationofmonoclonalantibodies
28. Computational biology and
forcancertherapy 331
model-based approaches in
Mechanismsofactionofantibodies
forcancertherapy 331 translational medicine 373
Fab-mediatedmechanismsofantibodies
Jo¨rgLippert,StefanWillmannandRolfBurghaus
forcancertherapy 331
Fc-mediatedmechanismsofantibodies Introduction:Modelbuildinginsciences 373
forcancertherapy 333 Compartmentalmodelingof
Engagingtheadaptiveimmuneresponse 334 pharmacokinetics:Aconceptualframework
Engagingantitumorimmuneresponses fortranslationalapplicationsinclinical
viacheckpointblockade 334 pharmacology 374
HarnessingIgE-mediatedimmune Physiologicallybasedmodeling:prediction
surveillanceagainstcancercells 335 ofpharmacokineticsinchildren 376
