State-of-the-art and emerging technologies for therapeutic monoclonal antibody characterization. Volume 1, Monoclonal antibody therapeutics: structure, function, and regulatory space

169 Pages·2014·2.33 MB·English

by  Borisov

State-of-the-Art and Emerging
Technologies for Therapeutic
Monoclonal Antibody Characterization
Volume 1. Monoclonal Antibody
Therapeutics: Structure, Function, and
Regulatory Space

1176
ACS SYMPOSIUM SERIES
State-of-the-Art and Emerging
Technologies for Therapeutic
Monoclonal Antibody Characterization
Volume 1. Monoclonal Antibody
Therapeutics: Structure, Function, and
Regulatory Space
John E. Schiel, Editor
National Institute of Standards and Technology
Gaithersburg, Maryland
Darryl L. Davis, Editor
Janssen Research and Development, LLC
Spring House, Pennsylvania
Oleg V. Borisov, Editor
Novavax, Inc.
Gaithersburg, Maryland

AmericanChemicalSociety,Washington,DC
DistributedinprintbyOxfordUniversityPress
LibraryofCongressCataloging-in-PublicationData
State-of-the-artandemergingtechnologiesfortherapeuticmonoclonalantibody
characterization/JohnE.Schiel,editor,NationalInstituteofStandardsandTechnology,
Gaithersburg,Maryland,DarrylL.Davis,editor,JanssenResearchandDevelopment,LLC,
SpringHouse,Pennsylvania,OlegV.Borisov,editor,Novavax,Inc.,Gaithersburg,
Maryland.
volumescm.-- (ACSsymposiumseries;1176)
Includesbibliographicalreferencesandindex.
Contents:v.1.monoclonalantibodytherapeutics:structure,function,andregulatoryspace
ISBN978-0-8412-3026-2
1. Monoclonalantibodies.2. Immunoglobulins--Therapeuticuse. I.Schiel,JohnE.,editor.
II.Davis,DarrylL.,editor.III.Borisov,OlegV.,editor.
QR186.85.S732014
616.07′98--dc23
2014040141
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Foreword
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Preface
Monoclonal antibodies (mAbs) are an important class of therapeutic that
has greatly expanded our ability to treat a variety of indications, including
cancer, autoimmune disorders, and infectious diseases. The cost of developing
these molecules and ensuring that they are fit for purpose is much higher than
for small-molecule drugs. Although some of these costs are due in part to the
nature of production, a major cost is incurred because of the complexity of the
molecule itself. Extensive analytical testing regimes are needed for in-depth
characterizationandtoensureproductstability,properin-processcontrols,safety,
and efficacy. The next generation of product understanding will require highly
complex, orthogonal technologies to elucidate interdependent structure-function
relationships.
Despite high development costs, the growth of mAb therapeutics continues
to soar, with sales of mAb-based therapeutics accounting for ~$50 billion U.S.
annually and for seven of the top-ten selling biologic drugs. In anticipation of
patentexpiryforsevenmajormAbtherapeuticspriorto2020,theU.S.Foodand
Drug Administration (FDA) released draft guidance on biosimilar approval in
2012. A landmark approval of the first mAb biosimilar occurred in 2013 when
the European Commission approved two biosimilar versions of infliximab. It
appearslikelythattheextensivepipelineofbiosimilarproductswillsoonbecome
a commercial reality on a global scale. The need for critical assessment of
therapeuticmAbcharacterizationisthereforeataprecipice,asitisexpectedthat
analyticalandbiophysicalcharacterizationstrategieswillplayanever-increasing
roleinbiosimilarityassessment.
Regardless of the pathway to market, the pursuit of improved public health
drives therapeutic development. Ultimately, assurance of public safety is of the
highestpriority. Consideringtheentiretyofadrug’slifecycle,thereisnogreater
need than for a suite of technologies capable of verifying mechanism of actions
(MoAs), identity, and the product and process consistency of such life-saving
medicines. Although characterization methods for mAbs continue to mature, a
holisticapproachcombiningamultitudeofscientificbackgroundsisrequiredfor
the characterization of various attributes of each individual drug candidate. To
that end, a manufacturer-specific repository of each drug must be retained as a
comparator to ensure consistent production over time. Although this approach
is indispensable, it also limits the ability for cross-agency harmonization of
industry best practices and limits collaboration across industry, government
agencies, academia, and instrument manufacturers. The unique challenge of
proteintherapeuticsresultedinaconsolidatedeffortbetweenindustry,academia,
and federal agencies to identify a means to better progress from drug target to
ix
therapy. Agroupofforward-thinkingindividualstestifiedbeforetheU.S.House
of Representatives Committee on Science and Technology in 2009 on behalf of
the biotherapeutic community regarding the need for better tools and the role
that standards can play. The seed was planted for a concerted effort toward
the development of appropriate standards and has continued to grow through
numerous workshops, seminars, and round-table discussions. Throughout this
time, it has become clear that researchers and regulators share a passion for
producingthehighestqualityproductsthroughcontrolledproductionandrobust
characterization.
Therigorsofbiotherapeuticdevelopmentandanalysishaveclearlyindicated
aneedforcontrolovereverystageofdevelopment. Criticalevaluationofprocess
steps and final product requires technique-specific standards to supplement the
in-house repository of specific drug substances. Constant dialogue between
industry,regulatorybodies,andstandardsorganizationshasidentifiedtheneedfor
standardsandassociateddatatobetterdefinemethodperformance. Theinformal
consortiumreferencedabove,alongwithyearsoftestingpotentialmethod-specific
standards, has shown that a class-specific molecule that embodies all of the
technicalchallengesofthatclassisnecessary. Therefore,anIgG1κwasselected
as the premier target capable of covering the broadest range of applications
and drug development targets. The mere presence of such a standard will not
guaranteesuccess;itwilltaketheunifiedeffortofallinvolvedtoincorporatesuch
a material into an already robust pipeline. The NIST mAb IgG1κ, as described
throughout this series, is being introduced as a collaborative tool to critically
evaluate current characterization strategies. The proposed reference material
showspromiseasamechanismforacceleratingnext-generationtechnologyinto
theroutinedevelopmentenvironment.
Scientific and health care advances have arisen throughout history, due in
parttobothdirectedscientificapproachesandasmalldoseofluck. Inevitably,it
isthecollaborativeeffortofmanywhohaveadvancedthisfieldtoarefinedstate
capable of meeting the global capacity and needs of the populous. The current
book series represents a defining moment in the development of technologies
forcharacterizingmAbs. Amultitudeofexpertsinthefieldhavecometogether
around a single molecule for the first time to demonstrate both current and

futurepracticesinvolvedinthecharacterizationofabiotherapeutic. Thecurrent

series presents an open discussion of current best practices, a multitude of
intuitive research, and a collaborative philosophy on where the field needs to
move to satisfy future scientific and regulatory needs. Throughout this effort,
a first-of-a-kind repository of regulatory considerations, experimental methods,
anddata—aswellasawidelyavailable“reference”mAb—arenowavailableto
industry,academia,regulatorypersonnel,andinstrumentmanufacturers. Wehope
thatthiscompilationservesasabaselineformanyyearsoffuturecollaboration,
continued development, and ultimately a routine analytical pipeline for rapid
time-to-marketformAbtherapeutics.
TheeditorsacknowledgeJaneLadnerforpreparationoftheNISTmAbmodel
structurefeaturedonthecover. ThismodelwasbuiltasdescribedinChapter1of
Volume3ofthisseries.
x
JohnE.Schiel
ResearchChemist
BiomolecularMeasurementDivision
NationalInstituteofStandardsandTechnology
Gaithersburg,Maryland20899,UnitedStates
[email protected](e-mail)
DarrylL.Davis
AssociateScientificDirector
JanssenResearchandDevelopment,LLC
SpringHouse,Pennsyvania19002,UnitedStates
[email protected](e-mail)
OlegV.Borisov
AssociateDirector
Novavax,Inc.
Gaithersburg,Maryland20878,UnitedStates
[email protected](e-mail)

xi
Editors’ Biographies
John E. Schiel
Dr. John E. Schiel received his B.S. (2004) and Ph.D. (2009) in Chemistry
from the University of Nebraska-Lincoln, and is currently a research chemist
in the NIST Biomolecular Measurement Division. He is leading the LC- and
MS-based biomanufacturing research efforts at NIST; developing a suite of
fundamental measurement science, standards, and reference data to enable
more accurate and confident characterization of product quality attributes. Dr.
Schiel is also the technical project coordinator for the recombinant IgG1κ NIST
monoclonalantibodyReferenceMaterial(NISTmAb)program. Heisanauthor
of over 20 publications and recipient of numerous awards, including the ACS
Division of Analytical Chemistry Fellowship, Bioanalysis Young Investigator
Award,andUNLEarlyAchieverAward.
Darryl L. Davis
Dr. Darryl L. Davis holds a doctorate in Medicinal Chemistry from the
Philadelphia College of Pharmacy and Science. His thesis focused on the use
of MS in the characterization and quantitation of peptide phosphorylation.
He started his career at J&J as a COSAT intern using MS to characterize the
glycan linkages found on Remicade. Upon receiving his doctorate he accepted
afull-timepositionwithintheBioanalyticalCharacterizationgroupatCentocor,
aJ&Jcompany. SincejoiningJ&Jhehasheldawidevarietyofresponsibilities
includingstartingandleadingseveralsub-groups,analyticalCMClead,member
of CDTs, member of technology development teams for alternative production
platformsandnewtechnologyandinnovationleadwithinanalyticaldevelopment.
He has won several innovation awards within J&J for his work on automation

andhigh-throughputanalysiswhichcontinuestobeacurrentfocus. Currentlyhe
leadsananalyticalgroupwithinthediscoveryorganizationatJanssenR&D.
Oleg V. Borisov
Dr. Oleg V. Borisov earned a B.S. degree (with honors) in Chemistry at
Moscow State University (1992), and received his Ph.D. in Chemistry from
Wayne State University (1997), after which he completed his post-doctoral
studiesatLawrenceBerkeleyNationalLaboratories(2000)andPacificNorthwest
NationalLaboratories(2001). Hisbackgroundincludesexperiencewithanalytical
methods for characterization of biotherapeutic proteins and vaccine products,
with emphasis on liquid chromatography and mass spectrometry methods.
©2014AmericanChemicalSociety
Dr. Borisov held positions at Genentech and Amgen with responsibilities that
included protein characterization, testing improvement, leading innovation and
CMC strategy teams. He is currently a Director at Novavax, Inc., developing
methodsandstrategiesforanalysisandcharacterizationofrecombinantvaccines,
based on nano- and virus-like particle technologies. His credits include several
studentawards,abookchapter,andover25scientificpublications.

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