Immunogenicity of Biopharmaceuticals (Biotechnology: Pharmaceutical Aspects)

269 Pages·2008·3.15 MB·English

by  Marco van de Weert

Immunogenicity of Biopharmaceuticals
Biotechnology: Pharmaceutical Aspects
VolumeI:PharmaceuticalProfilinginDrugDiscoveryforLeadSelection
R.T. Borchardt, E.H. Kerns, C.A. Lipinski, D.R. Thakker, B. Wang
Volume II: Lypophilization of Biopharmaceuticals
H.R. Constantino, M.J. Pikal
Volume III: Methods for Structural Analysis of Protein Pharmaceuticals
W. Jiskoot, D.J.A. Crommelin
Volume IV: Optimizing the “Drug-Like” Properties of Leads in Drug
Discovery
R.T. Borchardt, E.H. Kerns, M.J. Hageman, D.R. Thakker, J.L.
Stevens
Volume V: Prodrugs: Challenges and Rewards, Parts 1 and 2
V.J. Stella, R.T. Borchardt, M.J. Hageman, R. Oliyai, H. Maag,
J.W. Tilley
Volume VI: Solvent Systems and Their Selection in Pharmaceutics and
Biopharmaceutics
P. Augustijns, M.E. Brewster
Volume VII: Drug Absorption Studies: In Situ, In Vitro and In Silico
Models
C. Ehrhardt, K.J. Kim
Volume VIII: Immunogenicity of Biopharmaceuticals
M. van de Weert, E. H. Møller
Immunogenicity
of Biopharmaceuticals
Marco van de Weert
UniversityofCopenhagen
Copenhagen,Denmark
Eva Horn Møller
UniversityofCopenhagen
Copenhagen,Denmark
Editors
MarcovandeWeert EvaHornMøller
UniversityofCopenhagen UniversityofCopenhagen
Copenhagen,Denmark Copenhagen,Denmark
[email protected] [email protected]
ISBN:978-0-387-75840-4 e-ISBN:978-0-387-75841-1
LibraryofCongressControlNumber:2007941403
©2008AmericanAssociationofPharmaceuticalScientists
All rights reserved. This work may not be translated or copied in whole or in part without
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Preface
The last few decades have seen a rapid rise in novel drugs that mimic the
compounds found in the body, such as peptides, proteins, oligonucleotides,
certaintherapeuticvaccinesandgenes.Theseproducts,especiallywhenderived
frombiotechnologicalprocessing,arecommonlyreferredtoas“biopharmaceu-
ticals”,althoughtheclassificationasbiopharmaceuticalsdiffersslightlybetween
EuropeandtheUSA.Currently,thesecompoundsconstituteabout50%ofall
newdrugsinpre-clinicaldevelopmentandabout25–30%ofallnewapproved
drugs.
Biopharmaceuticalsarestrikinglydifferentfromlowmolecularweightdrugs.
Their delicate and complex nature, as well as their poor absorption through
biological membranes, renders them a tough challenge for the scientist that
wants to develop a rugged therapeutic for the market. As a result, delivery of
thesecompoundsisusuallybyinjectionorinfusion,andtheformulationisoften
uniqueforeachnewbiopharmaceutical.Someoftheanalyticalandformulation
challengesofbiopharmaceuticalshavebeenaddressedintwopreviousvolumes
intheseseries(volumeII:LyophilizationofBiopharmaceuticalsandvolumeIII:
MethodsforStructuralAnalysisofProteinPharmaceuticals).
Biopharmaceuticalsalsointroduceanotherchallenge,usuallyabsentforlow
molecular weight drugs, which is the ability to provoke an unwanted immune
response. This immune response not only can reduce the effectiveness of the
therapy, but can also lead to serious and life-threatening side-effects. Most
biopharmaceuticals are to some extent immunogenic, and as a result the
regulatory agencies insist that for protein pharmaceuticals potential antidrug
antibodyformationisstudiedduringdrugdevelopment.
As many patents are expiring for first-generation biopharmaceuticals,
biogenericproducts(alsotermedbiosimilars)areapproachingthemarket.The
riskofanimmuneresponseisamajorconcernindevelopmentofthesebiosim-
ilars,especiallysincebiopharmaceuticalsareoftentoocomplextocharacterize
infulldetail.Minordifferencesbetweentwoproductsmay,however,leadtoa
bigdifferenceinimmunogenicity,whichmaynotbepickedupinsmallclinical
trialsofshortduration.
The focus of this book is this potential unwanted immune response to
biopharmaceuticals. The book is essentially divided into three parts: The first
fivechaptersgiveageneraloverviewofthenature,causesand(clinical)impli-
cations of immunogenicity of biopharmaceuticals, as well as of the prediction
and analysis of immunogenicity. The next six chapters present specific cases
of immune responses to biopharmaceuticals. The final chapter contains a
v
vi Preface
discussiononriskmanagementofpotentialunwantedimmunogenicityduring
thedrugdevelopmentprocess.
The reader will note that the primary focus in all but one chapter is on
unwanted immunogenicity of protein pharmaceuticals. This is due to the fact
that these constitute the vast majority of biopharmaceutical products and that
experience with other biopharmaceuticals is very limited. However, we believe
that the concepts discussed in this book will be valid for non-protein biophar-
maceuticalsalso.
Regrettably, this book cannot give a definite answer to the question what
factorscauseunwantedimmunogenicity,andwhattodoaboutit.Ourinsights
into many of the mechanisms are still too limited to provide a clear answer.
However,thebookoutlinesthepresentstateofknowledgeandprovidessome
potentialexplanationsandcaveats.
Thebookshouldassistthoseworkinginearlydrugdevelopmentofbiophar-
maceuticals and allow them to define potential areas of concern as early as
possible. It will also serve the formulation scientist, who is responsible for
preparing a stable and safe product. Awareness of some of the risk factors
for immunogenicity development can aid in preventing future failure of the
product. Pharmacologists and clinicians working with biopharmaceuticals may
alsobenefitfromthisbook,asitgivespotentialexplanationsforseveralobser-
vations and provides discussions on the methodology used to determine and
quantifytheimmuneresponse.Finally,thebookwillbeofinteresttoacademics,
from M.Sc. upwards, working with biopharmaceuticals. It shows that there is
stillmuchtolearninthisarea,anditcontainsanumberofwarningsforthose
developingnovelbiopharmaceuticalsandadvanceddrugdeliverysystems.
Theeditorshopethatthisbookwillcontributetothedevelopmentofbetter
and safer biopharmaceuticals. We also hope that this book can promote a
concertedeffortinelucidatingtheimportantriskfactorsthatleadtoimmuno-
genicity.
Marco van de Weert
Eva Horn Møller
Contents
1. Immune Reactions Towards Biopharmaceuticals – a General,
Mechanistic Overview.......................................... 1
Camilla Foged and Anne Sundblad
2. Clinical Aspects of Immunogenicity to Biopharmaceuticals........ 27
Simona Malucchi and Antonio Bertolotto
3. Assessment of Unwanted Immunogenicity....................... 57
Meenu Wadhwa and Robin Thorpe
4. Models for Prediction of Immunogenicity........................ 75
Erwin L. Roggen
5. Immunogenicity of Biopharmaceuticals: Causes, Methods
to Reduce Immunogenicity, and Biosimilars...................... 97
Marco van de Weert and Eva Horn Møller
6. Case Study: Immunogenicity of rhEPO..........................113
Arno Kromminga and Gilbert Deray
7. Case Study: Immunogenicity of Interferon-Beta..................127
Klaus Bendtzen and Arno Kromminga
8. Case Study: Immunogenicity of Insulin..........................137
Henriette Mersebach, Fannie Smith, Thomas Sparre
and Lisbeth Bjerring Jensen
9. Case Study: Immunogenicity of Factor VIII......................147
Silke Ehrenforth and Stephanie Seremetis
10. Case Study: Immunogenicity of Natalizumab.....................173
Meena Subramanyam
11. Case Study: Immunogenicity of Anti-TNF Antibodies ............ 189
Klaus Bendtzen
12. Heparin-Induced Thrombocytopenia.............................205
Carmel A. Celestin and John R. Bartholomew
13. Presenting an Immunogenicity Risk Assessment to Regulatory
Agencies......................................................239
Paul Chamberlain
Subject Index..................................................259
vii
Contributors
John R. Bartholomew
Section of Vascular Medicine, Department of Cardiovascular Medicine,
Cleveland Clinic, Cleveland, OH, United States of America
E-mail: [email protected]
Klaus Bendtzen
Institute for Inflammation Research (IIR), Rigshospitalet National
University Hospital, BioMonitor ApS, Copenhagen, Denmark
E-mail: [email protected]
Antonio Bertolotto
Centro di Riferimento Regionale Sclerosi Multipla, Hospital San Luigi,
Orbassano, Turin, Italy
E-mail: [email protected]
Carmel A. Celestin
Section of Vascular Medicine, Department of Cardiovascular Medicine,
Cleveland Clinic, Cleveland, OH, United States of America
E-mail: [email protected]
Paul Chamberlain
bioLOGICA Consulting, France
E-mail: [email protected]
Gilbert Deray
Groupe Hospitalier Pitié-Salpeˆtrière, Paris, France
E-mail: [email protected]
Silke Ehrenforth
Global Development, Novo Nordisk A/S, Bagsværd, Denmark
E-mail: [email protected]
Camilla Foged
Department of Pharmaceutics and Analytical Chemistry, Faculty of
Pharmaceutical Sciences, University of Copenhagen, Copenhagen,
Denmark
E-mail: [email protected]
ix
x Contributors
Lisbeth Bjerring Jensen
Global Development, Antibody Analysis, Novo Nordisk A/S, Måløv,
Denmark
E-mail: [email protected]
Arno Kromminga
Institute for Immunology, Clinical Pathology, Molecular Medicine (IPM),
Hamburg, Germany
E-mail: [email protected]
Simona Malucchi
Centro di Riferimento Regionale Sclerosi Multipla, Hospital San Luigi,
Orbassano, Turin, Italy
E-mail: [email protected]
Henriette Mersebach
Global Development, Novo Nordisk A/S, Bagsværd, Denmark
E-mail: [email protected]
Eva Horn Møller
Department of Pharmaceutics and Analytical Chemistry, Faculty of
Pharmaceutical Sciences, University of Copenhagen, Copenhagen,
Denmark
E-mail: [email protected]
Erwin L Roggen
Novozymes AS, Bagsværd, Denmark
E-mail: [email protected]
Stephanie Seremetis
Global Development, Novo Nordisk A/S, Bagsværd, Denmark
E-mail: [email protected]
Fannie Smith
Global Development, Novo Nordisk A/S, Bagsværd, Denmark
E-mail: [email protected]
Thomas Sparre
Global Development, Novo Nordisk A/S, Bagsværd, Denmark
E-mail: [email protected]
Meena Subramanyam
Biogen Idec, Inc., Cambridge, MA, United States of America
E-mail: [email protected]
Anne Sundblad
Department of Medicine, Division of Hematology, Karolinska University
Hospital and Institute, Stockholm, Sweden
E-mail: [email protected]