Recombinant Antibodies for Immunotherapy

444 Pages·2009·6.66 MB·English

by  Melvyn Little PhD

RECOMBINANTANTIBODIESFORIMMUNOTHERAPY
RecombinantAntibodiesforImmunotherapyprovidesacomprehensive
overview of the field of monoclonal antibodies (mAbs), a market that
has grown tremendously in recent years. Twenty-four chapters by
experienced and innovative authors cover the isolation of specific
human mAbs, humanization, immunogenicity, technologies for
improving efficacy, ‘‘arming’’ mAbs, novel alternative Ab constructs,
increasing half-lives, alternative concepts employing non-immuno-
globulin scaffolds, novel therapeutic approaches, a market analysis
oftherapeuticmAbs,andfuturedevelopmentsinthefield.
The concepts and technologies are illustrated by examples of
recombinant antibodies being used in the clinic or in development.
This book will appeal to both newcomers and experienced scientists
inthefield,biologyandbiotechnologystudents,researchanddevelop-
ment departments in the pharmaceutical industry, medical research-
ers,clinicians,andbiotechnologyinvestors.
MelvynLittle’sresearchgroupattheGermanCancerResearchCenter
(DKFZ)inHeidelbergwasoneofthefirsttodevelopmethodsformak-
ingandscreeningantibodylibraries.Afterco-foundingAffitech(Oslo,
Norway)in1997,helefttheDKFZin2000tofoundAffimedTherapeu-
tics,abiotechnologycompanyinHeidelbergspecializingintheisola-
tion and engineering of human antibodies to treat various diseases,
especially cancer. He has been an extracurricular professor of bio-
chemistryattheUniversityofHeidelbergsince1986.

RECOMBINANT ANTIBODIES
FOR IMMUNOTHERAPY
Edited by
Melvyn Little
Affimed Therapeutics
CAMBRIDGEUNIVERSITYPRESS
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Cambridge University Press
The Edinburgh Building, Cambridge CB2 8RU, UK
Published in the United States of America by Cambridge University Press, New York
www.cambridge.org
Information on this title: www.cambridge.org/9780521887328
© Cambridge University Press 2009
This publication is in copyright. Subject to statutory exception and to the
provision of relevant collective licensing agreements, no reproduction of any part
may take place without the written permission of Cambridge University Press.
First published in print format 2009
ISBN-13 978-0-511-59637-7 eBook (NetLibrary)
ISBN-13 978-0-521-88732-8 Hardback
Cambridge University Press has no responsibility for the persistence or accuracy
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and does not guarantee that any content on such websites is, or will remain,
accurate or appropriate.
Information regarding prices, travel timetables, and other factual information
given in this work are correct at the time of first printing, but Cambridge
University Press does not guarantee the accuracy of such information thereafter.
Every effort has been made in preparing this book to provide accurate and up-to-
date information that is in accord with accepted standards and practice at the time
of publication. Nevertheless, the authors, editors, and publisher can make no
warranties that the information contained herein is totally free from error, not least
because clinical standards are constantly changing through research and
regulation. The authors, editors, and publisher therefore disclaim all liability for
direct or consequential damages resulting from the use of material contained in
this book. Readers are strongly advised to pay careful attention to information
provided by the manufacturer of any drugs or equipment that they plan to use.
Contents
Contributors pagevii
ForewordbySirGregoryWinter xi
Preface xiii
PART I. HUMANIZED ANTIBODIES
1 HumanizationofRecombinantAntibodies 3
Jose´W.Saldanha
2 ImmunogenicityAssessmentofAntibodyTherapeutics 20
PhilippeStas,JurgenPletinckx,YannickGansemans,andIgnaceLasters
3 InVitroScreeningforAntibodyImmunogenicity 43
FrankJ.CarrandMatthewP.Baker
PART II. GENERATION AND SCREENING OF ANTIBODY LIBRARIES
4 AntibodyLibrariesfromNa¨ıveVGeneSources 55
GeraldBesteandDavidLowe
5 Antibodies from IgM Libraries 66
StefanKnackmussandVeraMolkenthin
6 GenerationandScreeningoftheSyntheticHumanCombinatorial
AntibodyLibraryHuCALGOLD 75
IngoM.Klagge
PART III. TRANSGENIC HUMAN ANTIBODY REPERTOIRES
7 TherapeuticAntibodiesfromXenoMouseTransgenicMice 89
AyaJakobovits
8 VelocImmune:ImmunoglobulinVariableRegionHumanizedMice 100
AndrewMurphy
PART IV. ANTIBODY EFFECTOR FUNCTION
9 MechanismsofTumorCellKillingbyTherapeuticAntibodies 111
RossStewartandCarlWebster
10 OptimizationofFcDomainstoEnhanceAntibodyTherapeutics 124
GregA.LazarandAaronK.Chamberlain
11 GlycoengineeredTherapeuticAntibodies 144
PeterBru¨nker,PeterSondermann,andPabloUman˜a
v
vi Contents
PART V. ARMING ANTIBODIES
12 MonoclonalAntibodiesfortheDeliveryofCytotoxicDrugs 157
DavidJ.King
13 ImmunotherapywithRadio-immuneConjugates 174
ChristinaA.KousparouandAgamemnonA.Epenetos
14 ImmunotherapeuticAntibodyFusionProteins 190
NigelS.Courtenay-LuckandDavidJones
PART VI. NOVEL ANTIBODY FORMATS
15 AlternativeAntibodyFormats 203
FabriceLeGallandMelvynLittle
16 Single-DomainAntibodies 216
SergeMuyldermans,GholamrezaHassanzadehGhassabeh,
andDirkSaerens
17 EngineeringofNon-CDRLoopsinImmunoglobulinDomains 231
FlorianRu¨kerandGordanaWozniak-Knopp
PART VII. ANTIGEN-BINDING REPERTOIRES OF NON-IMMUNOGLOBULIN PROTEINS
18 AlternativeScaffolds:ExpandingtheOptionsofAntibodies 243
AndreasPlu¨ckthun
PART VIII. PROLONGATION OF SERUM HALF-LIFE
19 PolymerFusionstoIncreaseAntibodyHalf-Lives:
PEGylationandOtherModifications 275
SamP.HeywoodandDavidP.Humphreys
20 ExtendingAntibodyFragmentHalf-LiveswithAlbumin 293
JanTerjeAndersenandIngerSandlie
PART IX. INNOVATIVE IMMUNOTHERAPEUTIC APPROACHES
21 AStemCell–BasedPlatformfortheDiscoveryandDevelopment
ofAntitumorTherapeuticAntibodiestoNovelTargets 313
JennieP.Mather,ClaudiaFieger,TonyW.Liang,KathleenL.King,
JonathanLi,PeterYoung,ClaudeBeltejar,BeverlyPotts,
MonicaLicea,andDerykLoo
22 AntibodyDirectedEnzymeProdrugTherapy(ADEPT) 336
HelenL.Lowe,SurinderK.Sharma,KennethD.Bagshawe,and
KerryA.Chester
23 ImmunePrivilegeandTolerance–TherapeuticAntibodyApproaches 350
DaronForman,PaulPonath,DevangiMehta,JoePonte,
JessicaSnyder,PatriciaRao,HermanWaldmann,and
MichaelRosenzweig
PART X. MARKET OVERVIEW AND OUTLOOK
24 AntibodyTherapeutics:BusinessAchievementsandBusinessOutlook 373
ChristopheBourrilly
Index 403
Colorplatesfollowpagexvi.
Contributors
JanTerjeAndersen KerryA.Chester
DepartmentofMolecularBiosciencesand CRUKTargeting&ImagingGroup
CentreforImmuneRegulation DepartmentofOncology
UniversityofOslo UCLCancerInstitute
Oslo,Norway UniversityCollegeLondon
London,U.K.
KennethD.Bagshawe
DepartmentofOncology NigelS.Courtenay-Luck
ImperialCollegeLondon AntisomaResearchLtd.
London,U.K. London,U.K.
MatthewP.Baker AgamemnonA.Epenetos
AntitopeLtd. TrojantecLtd.
Babraham,Cambridge,U.K. Nicosia,Cyprus
ClaudeBeltejar ClaudiaFieger
RavenBiotechnologies RavenBiotechnologies
SanFrancisco,California,U.S. SanFrancisco,California,U.S.
GeraldBeste DaronForman
formerlyMedImmuneLtd. Tolerx
Cambridge,U.K. Cambridge,Massachusetts,U.S.
nowAblynxNV
Ghent,Belgium YannickGansemans
AlgonomicsNV
ChristopheBourrilly Gent-Zwijnaarde,Belgium
ABNAMROCorporateFinanceLtd.
GholamrezaHassanzadehGhassabeh
London,U.K.
LaboratoryofCellularandMolecular
PeterBru¨nker Immunology
GlycartBiotechnology(RocheGroup) VrijeUniversiteit
Schlieren,Switzerland andDepartmentofMolecularandCellular
Interaction
FrankJ.Carr VIB
AntitopeLtd. Brussels,Belgium
Babraham,Cambridge,U.K.
SamP.Heywood
AaronK.Chamberlain AntibodyResearch
Xencor UCB-Celltech
Monrovia,California,U.S. Slough,U.K.
vii
viii Contributors
DavidP.Humphreys MonicaLicea
AntibodyResearch RavenBiotechnologies
UCB-Celltech SanFrancisco,California,U.S.
Slough,U.K.
MelvynLittle
AyaJakobovits
AffimedTherapeuticsAG
Agensys,Inc.
Heidelberg,Germany
SantaMonica,California,U.S.
DavidJones
DerykLoo
AntisomaResearchLtd.
RavenBiotechnologies
London,U.K.
SanFrancisco,California,U.S.
DavidJ.King
formerlyMedarex DavidLowe
Sunnyvale,California,U.S. MedImmuneLtd.
nowAnaptysBioInc. Cambridge,U.K.
SanDiego,California,U.S.
HelenL.Lowe
KathleenL.King
CRUKTargeting&ImagingGroup
RavenBiotechnologies
DepartmentofOncology
SanFrancisco,California,U.S.
UCLCancerInstitute
IngoM.Klagge UniversityCollegeLondon
MorphoSysAG London,U.K.
Martinsried/Planegg,Germany
JennieP.Mather
StefanKnackmuss
RavenBiotechnologies
AffimedTherapeuticsAG
SanFrancisco,California,U.S.
Heidelberg,Germany
ChristinaA.Kousparou
DevangiMehta
TrojantecLtd.
Tolerx
Nicosia,Cyprus
Cambridge,Massachusetts,U.S.
IgnaceLasters
AlgonomicsNV VeraMolkenthin
Gent-Zwijnaarde,Belgium AffimedTherapeuticsAG
Heidelberg,Germany
GregA.Lazar
Xencor
AndrewMurphy
Monrovia,California,U.S.
Regeneron
FabriceLeGall Tarrytown,NewYork,U.S.
AffimedTherapeuticsAG
Heidelberg,Germany
SergeMuyldermans
LaboratoryofCellularandMolecular
JonathanLi
Immunology
RavenBiotechnologies
VrijeUniversiteit
SanFrancisco,California,U.S.
andDepartmentofMolecularand
TonyW.Liang CellularInteraction
RavenBiotechnologies VIB
SanFrancisco,California,U.S. Brussels,Belgium
Contributors ix
JurgenPletinckx IngerSandlie
AlgonomicsNV DepartmentofMolecular
Gent-Zwijnaarde,Belgium BiosciencesandCentreforImmuneRegulation
UniversityofOslo
AndreasPlu¨ckthun Oslo,Norway
DepartmentofBiochemistry
UniversityofZu¨rich SurinderK.Sharma
Zurich,Switzerland CRUKTargeting&ImagingGroup
DepartmentofOncology
PaulPonath UCLCancerInstitute
Tolerx UniversityCollegeLondon
Cambridge,Massachusetts,U.S. London,U.K.
JessicaSnyder
JoePonte
Tolerx
Tolerx
Cambridge,Massachusetts,U.S.
Cambridge,Massachusetts,U.S.
PeterSondermann
BeverlyPotts
GlycartBiotechnology(RocheGroup)
RavenBiotechnologies
Schlieren,Switzerland
SanFrancisco,California,U.S.
PhilippeStas
PatriciaRao AlgonomicsNV
formerlyTolerx Gent-Zwijnaarde,Belgium
Cambridge,Massachusetts,U.S.
nowSyntaPharmaceuticalCorp. RossStewart
Lexington,Massachusetts,U.S. MedImmuneLtd.
Cambridge,U.K.
MichaelRosenzweig
Tolerx PabloUman˜a
Cambridge,Massachusetts,U.S. GlycartBiotechnology(RocheGroup)
Schlieren,Switzerland
FlorianRu¨ker
HermanWaldmann
DepartmentofBiotechnology
formerlyTolerx
UniversityofNaturalResources
Cambridge,Massachusetts,U.S.
andAppliedLifeSciences
nowSirWilliamDunnSchoolofPathology
Vienna,Austria
Oxford,U.K.
DirkSaerens
CarlWebster
LaboratoryofCellularandMolecular
MedImmuneLtd.
Immunology
Cambridge,U.K.
VrijeUniversiteit
andDepartmentofMolecularandCellular GordanaWozniak-Knopp
Interaction DepartmentofBiotechnology
VIB UniversityofNaturalResources
Brussels,Belgium andAppliedLifeSciences
Vienna,Austria
Jose´ W.Saldanha
DivisionofMathematicalBiology PeterYoung
NationalInstituteforMedicalResearch RavenBiotechnologies
MillHill,London,U.K. SanFrancisco,California,U.S.