Heterogeneityandcomplexityofbiopharmaceuticalagentsdevelopedoverthepastdecadeorsocanbedefined attwolevels.First,inthecaseofproteinsystemssuchasmonoclonalantibodies,theprimarysourceofheterogeneity arises from glycosylation post?translational modifications mainly at the conserved N?linked glycosylation sites in the constant (Fc) region of the heavy chain. The Fc glycosylation plays a role in maintaining antibody stability and also contributes to binding with Fc gamma receptor isoforms that in turn mediate effector functions such as antibody dependentcellularcytotoxicity(ADCC).Second,inthecaseofcomplexdrugssuchasheparinorlowmolecularweight heparin(LMWH)etc.themaincomponentofthedrugisaheterogeneousmixtureoflinear(inthecaseofheparin)or branchedglycanpolymerswithamolecularweightandanionicchargedistribution.Developingfollow?on(orgeneric) versionsofsuchcomplexbiopharmaceuticalmixturesisthereforeinconstantneedfornewtechnologiestodefineand characterizethesemixturesascomprehensivelyaspossiblefromthestandpointofchemicalandbiologicalequivalence. Despite these advances, there remain gaps in linking glycosylation heterogeneity with antibody efficacy and adverseeffectssuchasthoserelatedtohostimmuneresponsetoahumanantibodygeneratedinanon?humancellline. InthecaseofcomplexglycandrugssuchasheparinandLMWH,thereisalargergapinlinkingmixturepropertieswith biologicalactionofthedrug.Forexample,despitethefactthatheparinhasbeenqualitycontrolledandusedinclinicfor severaldecades,aseriousglobalhealthcrisisassociatedwithadministrationofheparinemergedinearlyMarch2008 whichwaslateridentifiedbyusandotherstobeassociatedwithanunnaturalglycosaminoglycancontaminantspecies. Wehaveextensiveexperienceincharacterizingcomplexbiopharmaceuticalmixturesintermsoftheirstructural attributes and how these attributes impinge on their function. A central component of our approach is the ability to employ a computational framework that we had built over the past decade or so in integrating diverse datasets pertaining to complex glycan mixtures. This framework permitted us to incorporate orthogonal datasets including analyticalandfunctionaldatatogettothebottomofstructure?functionrelationshipsofcomplexglycanmixtures.Inthis proposal we seek to build on this computational platform and our extensive experience to build a robust set of integrated tools and algorithms to determine the extent of characterization required for establishing equivalence for therapeuticsthatareusedintheclinic.Throughthestudiesproposedhere,webelievethatwewillmakeacontribution towards determining criteria for sufficiency in characterization of complex therapeutic agents in establishing equivalence.

Public Health Relevance

Developing follow-on (or generic) versions of such complex biopharmaceutical mixtures is in constant need for new technologiestodefineandcharacterizethesemixturesascomprehensivelyaspossiblefromthestandpointofchemicaland biologicalequivalence.Buildingonourextensiveexperienceindevelopingcomputationaltools,hereinweaimtoconstruct a robust set of integrated algorithms or `tools' to determine the extent of characterization required for establishing equivalence of therapeutics used in the clinic. Through the studies proposed here, we believe that we will make a contributiontowardsdeterminingcriteriaforsufficiencyincharacterizationofcomplextherapeuticpharmaceuticalagents

Agency
National Institute of Health (NIH)
Institute
Food and Drug Administration (FDA)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01FD005291-01
Application #
8881515
Study Section
Special Emphasis Panel (ZFD1-SRC (99))
Project Start
2014-09-10
Project End
2017-08-31
Budget Start
2014-09-10
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Type
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02142