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dc.contributor.authorPiche-Nicholas, Nicole Melissaen_US
dc.date.accessioned2016-02-11T15:23:16Z
dc.date.available2016-02-11T15:23:16Z
dc.date.issued2014
dc.identifier.urihttps://hdl.handle.net/2144/14377
dc.description.abstractA large body of data exists demonstrating the key role of FcRn in extending the half-life of therapeutic antibodies by rescuing them from lysosomal degradation. This led to the widely accepted hypothesis that FcRn binding of an IgG via the CH2-CH3 interface of Fc correlates with IgG half-life. Several studies have demonstrated that in vivo half-life can be modified by changing the binding affinity of IgG to FcRn. These modifications were generated by mutating the coding sequence for the Fc region that resulted in enhanced or reduced FcRn binding at endosomal pH without enhancing binding at neutral pH. In contrast to this, we have observed that the half-lifes of IgG molecules that had showed no target-mediated disposition or off-target binding varies widely, even when they share identical Fc domains. This led us to hypothesize that domains of IgG molecules other than Fc could contribute to the modulation of FcRn binding and affect in vivo half-life. This hypothesis was strengthened by recent publications by other groups showing a correlation between antibody charge and the FcRn affinity and/or in vivo half-life. In this study we explored the role of IgG domains other than the FcRn binding domain in altering the affinity between IgG and FcRn and its relation to the in vivo half-life. Here we describe a surface plasmon resonance (SPR) based assay developed to examine the steady-state binding affinity (KD) of IgG molecules to FcRn. We systematically dissected the contributions of IgG variable domain regions in modulating the affinity between FcRn and IgG. Through analysis of a broad collection of therapeutic antibodies containing more than 100 unique IgG molecules against more than 25 different therapeutic targets we have demonstrated that variable domains and in particular CDRs significantly alter binding affinity to FcRn, by 10 to 80-fold, whereas heavy and light chain isotypes do not. Because CDRs modulate the affinity between IgG and FcRn in our in vitro studies, it is important to understand the role they play in modulation of IgG half-life in vivo as this would have far-reaching implications in the half-life optimization efforts of IgG therapeutics.en_US
dc.language.isoen_US
dc.subjectPharmacologyen_US
dc.subjectFcRnen_US
dc.subjectIgGen_US
dc.subjectNeonatal Fc receptoren_US
dc.titleChanges in complementarity-determining regions significantly alter IgG binding to the neonatal Fc receptoren_US
dc.typeThesis/Dissertationen_US
dc.date.updated2016-01-22T18:56:37Z
etd.degree.nameM.A.en_US
etd.degree.levelmastersen_US
etd.degree.disciplinePharmacology & Experimental Therapeuticsen_US
etd.degree.grantorBoston Universityen_US


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