Antibody-Drug Conjugates

329 Pages·2013·4.796 MB·English

by  Ingrid Sassoon, Véronique Blanc (auth.), Laurent Ducry (eds.)

Methods in
Molecular Biology 1045
Laurent Ducry Editor
Antibody-Drug
Conjugates
M M B TM
ETHODS IN OLECULAR IOLOGY
SeriesEditor
JohnM.Walker
School ofLife Sciences
University ofHertfordshire
Hatfield, Hertfordshire,AL109AB,UK
For further volumes:
http://www.springer.com/series/7651
.
Antibody-Drug Conjugates
Edited by
Laurent Ducry
Lonza Ltd, Visp, Switzerland
Editor
LaurentDucry
LonzaLtd
Visp,Switzerland
ISSN1064-3745 ISSN1940-6029(electronic)
ISBN978-1-62703-540-8 ISBN978-1-62703-541-5(eBook)
DOI10.1007/978-1-62703-541-5
SpringerNewYorkHeidelbergDordrechtLondon
LibraryofCongressControlNumber:2013943693
#SpringerScience+BusinessMedia,LLC2013
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Preface
Antibody–drugconjugates(ADCs)representapromisingtherapeuticapproachforcancer
patients by combining the antigen-targeting specificity of monoclonal antibodies (mAbs)
®
with the cytotoxic potency of chemotherapeutic drugs. The FDA approval of Adcetris
®
(brentuximabvedotin)in2011andKadcyla (trastuzumabemtansineorT-DM1)in2013
hasvalidatedtheideaofmaking“armed”antibodies,attractingalotofattentionintothis
field. ADC technology has been an active area of research in recent years, resulting in a
numberofADCsindevelopmentfor varioustumor types.Thenumberofimmunoconju-
gatesorADCsundergoingclinicaltrialwillthusfurtherincrease,possiblyreplacingsome
of the existing naked monoclonal antibodies, and becoming the next generation of
anticancerbiotherapeutics.
AlthoughtheADCconceptisquitesimple,successfullydesigninganddevelopingsuch
a“smartbomb”isacomplextask.Despiteatremendousincreaseinourunderstandingin
recentyears,alotofworkisnecessaryinordertoidentifyasuitabletarget;properlydesign
the mAb, the linker, and the payload; as well as conjugate them in a reproducible and
scalablefashion.
The success of the current conjugation technologies has been achieved thanks to the
developmentofnewmethodologies.Theaimofthisbookistoprovidedetailedprotocols
for many of the key ADC techniques necessary for working in the field. Each method is
described by an author who has regularly used the technique in his or her laboratory. In
addition, several review chapters are included to summarize the current knowledge and
results in the ADC area. These should make this book useful to readers with no previous
ADC experience as well as those already working in the field. It is my hope that this
publicationwill further drive ADC development and thus help towardsimproving cancer
treatmentsofthefuture.
Visp,Switzerland LaurentDucry
v

Contents
Preface.................................................................... v
Contributors............................................................... ix
1 Antibody–DrugConjugate(ADC)ClinicalPipeline:AReview.............. 1
IngridSassoonandVe´roniqueBlanc
2 Antibody–DrugConjugateTargetSelection:CriticalFactors ............... 29
NeilH.Bander
3 SelectinganOptimalAntibodyforAntibody–DrugConjugateTherapy:
InternalizationandIntracellularLocalization ............................. 41
JayHarper,ShenlanMao,PatrickStrout,andAdeelaKamal
4 Antibody–DrugConjugatePayloads..................................... 51
JanAnderl,HeinzFaulstich,TorstenHechler,andMichaelKulke
5 LinkerTechnologiesforAntibody–DrugConjugates ...................... 71
BirteNolting
6 InVivoTestingofDrug-LinkerStability ................................. 101
Pierre-YvesAbecassisandCe´lineAmara
7 PharmacokineticsandADMECharacterizations
ofAntibody–DrugConjugates.......................................... 117
KedanLin,JayTibbitts,andBen-QuanShen
8 SafeHandlingofCytotoxicCompoundsinaBiopharmaceutical
Environment.......................................................... 133
MiriamI.HensgenandBernhardStump
9 Micro-andMid-ScaleMaleimide-BasedConjugationofCytotoxic
DrugstoAntibodyHingeRegionThiolsforTumorTargeting ............. 145
JamesE.Stefano,MichelleBusch,LihuiHou,AnnaPark,
andDiegoA.Gianolio
10 ProtocolsforLysineConjugation ....................................... 173
Marie-PriscilleBrunandLaurenceGauzy-Lazo
11 EngineeringTHIOMABsforSite-SpecificConjugation
ofThiol-ReactiveLinkers............................................... 189
SunilBhakta,HelgaRaab,andJagathR.Junutula
12 EnzymaticAntibodyModificationbyBacterialTransglutaminase............ 205
PatrickDennler,RogerSchibli,andElianeFischer
13 FormulationDevelopmentofAntibody–DrugConjugates ................. 217
WilliamJ.GalushandAdityaA.Wakankar
14 ConjugationProcessDevelopmentandScale-Up ......................... 235
BernhardStumpandJessicaSteinmann
15 MethodsforConjugatingAntibodiestoNanocarriers ..................... 249
AnilWaghandBenedictLaw
16 Drug-to-AntibodyRatio(DAR)byUV/VisSpectroscopy ................. 267
YanChen
vii
viii Contents
17 Drug-to-AntibodyRatio(DAR)andDrugLoadDistribution
byHydrophobicInteractionChromatographyandReversedPhase
High-PerformanceLiquidChromatography.............................. 275
JunOuyang
18 Drug-to-AntibodyRatio(DAR)andDrugLoadDistribution
byLC-ESI-MS........................................................ 285
LouisetteBasa
19 DeterminationofChargeHeterogeneityandLevelofUnconjugated
AntibodybyImagedcIEF.............................................. 295
JoyceLinandAlexandruC.Lazar
20 Risk-BasedScientificApproachforDetermination
ofExtractables/LeachablesfromBiomanufacturing
ofAntibody–DrugConjugates(ADCs) .................................. 303
WeibingDing
Index..................................................................... 313
Contributors
PIERRE-YVES ABECASSIS (cid:1) DSAR (Disposition, Safety & Animal Research), Sanofi,
Vitry-sur-Seine, France
CE´LINE AMARA (cid:1) DSAR (Disposition, Safety & Animal Research), Sanofi,
Vitry-sur-Seine, France
JAN ANDERL (cid:1) Heidelberg Pharma GmbH, Ladenburg, Germany
NEIL H. BANDER (cid:1) Weill-Cornell Medical College, Cornell University, New York,
NY, USA
LOUISETTE BASA (cid:1) Protein Analytical Chemistry, Genentech Inc., South San Francisco,
CA, USA
SUNIL BHAKTA (cid:1) Genentech Inc., South San Francisco, CA, USA
VE´RONIQUE BLANC (cid:1) Sanofi Oncology, Vitry-sur-Seine, France
MARIE-PRISCILLE BRUN (cid:1) Natural Product and Protein Chemistry, Sanofi,
Vitry-sur-Seine, France
MICHELLEBUSCH (cid:1) TransitionalResearch,Genzyme,aSanofiCompany,Framingham,
MA, USA
YAN CHEN (cid:1) Protein Analytical Chemistry, Genentech Inc., South San Francisco,
CA, USA
PATRICK DENNLER (cid:1) Center for Radiopharmaceutical Sciences, Paul Scherrer Institute,
Villigen, Switzerland
WEIBING DING (cid:1) SLS Global Technical Support, Pall Corporation, Port Washington,
NY, USA
HEINZ FAULSTICH (cid:1) Heidelberg Pharma GmbH, Ladenburg, Germany
ELIANE FISCHER (cid:1) Center for Radiopharmaceutical Sciences, Paul Scherrer Institute,
Villigen, Switzerland
WILLIAM J. GALUSH (cid:1) Early Stage Pharmaceutical Development, GenentechInc.,
South San Francisco, CA, USA
LAURENCE GAUZY-LAZO (cid:1) Natural Product and Protein Chemistry, Sanofi,
Vitry-sur-Seine, France
DIEGO A. GIANOLIO (cid:1) Drugs and Biomaterials R&D, Genzyme, a Sanofi Company,
Cambridge, MA, USA
JAY HARPER (cid:1) Oncology Research, MedImmune Inc., Gaithersburg, MD, USA
TORSTEN HECHLER (cid:1) Heidelberg Pharma GmbH, Ladenburg, Germany
MIRIAM I. HENSGEN (cid:1) Bioconjugates R&D, Lonza Ltd, Visp, Switzerland
LIHUI HOU (cid:1) Transitional Research, Genzyme, a Sanofi Company, Framingham,
MA, USA
JAGATH R. JUNUTULA (cid:1) Genentech Inc., South San Francisco, CA, USA
ADEELA KAMAL (cid:1) Oncology Research, MedImmune Inc., Gaithersburg, MD, USA
MICHAEL KULKE (cid:1) Heidelberg Pharma GmbH, Ladenburg, Germany
BENEDICT LAW (cid:1) Department of Pharmaceutical Sciences, College of Pharmacy,
Nursing and Allied Sciences, North Dakota State University, Fargo, ND, USA
ALEXANDRU C. LAZAR (cid:1) Analytical & Pharmaceutical Sciences, ImmunoGen,
Inc., Waltham, MA, USA
ix