Anti-Aβ Oligomer IgG and Surface Sialic Acid in Intravenous Immunoglobulin: Measurement and Correlation with Clinical Outcomes in Alzheimer’s Disease Treatment

Kwon, Hyewon; Crisostomo, Amanda C.; Smalls, Hayley Marie; Finke, John M.

doi:10.1371/journal.pone.0120420

Cited by 12 publications

(22 citation statements)

References 66 publications

(134 reference statements)

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“…Both global and local fits were performed. Based on published ELISA results and SPR calibration free concentration analysis [21], the natural Ab + IgG concentration in IVIG used for fitting was 60 nM [8,22].…”

Section: Spr Analysismentioning

confidence: 99%

Kinetic analysis of IgG antibodies to beta-amyloid oligomers with surface plasmon resonance

Crisostomo

Dang

Digambaranath

et al. 2015

Analytical Biochemistry

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Surface plasmon resonance was used to investigate the kinetics, affinity, and specificity of binding between anti-Aβ (beta-amyloid) IgG antibodies and oligomeric Aβ. Two factors were needed to accurately characterize the IgG binding kinetics. First, a bivalent model was necessary to properly fit the kinetic association and dissociation sensograms. Second, a high concentration of IgG was necessary to overcome a significant mass transport limitation that existed regardless of oligomer density on the sensor surface. Using high IgG concentrations and bivalent fits, consistent kinetic parameters were found at varying sensor surface ligand densities. A comparison of binding specificity, affinity, and kinetic flux between monoclonal and natural human anti-Aβ IgG antibodies revealed the following findings. First, monoclonal antibodies 6E10 and 4G8 single-site binding affinity is similar between Aβ oligomers and monomers. Second, natural human anti-Aβ IgG binding readily binds Aβ oligomers but does not bind monomers. Third, natural human anti-Aβ IgG binds Aβ oligomers with a higher affinity and kinetic flux than 6E10 and 4G8. Both the current analytical methodology and antibody binding profiles are important for advances in antibody drug development and kinetic biomarker applications for Alzheimer's disease.

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Section: Spr Analysismentioning

confidence: 99%

Kinetic analysis of IgG antibodies to beta-amyloid oligomers with surface plasmon resonance

Crisostomo

Dang

Digambaranath

et al. 2015

Analytical Biochemistry

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“…This finding is somewhat surprising given that both mAbs 6E10 and 4G8 exhibit a similar affinity towards the same target, although different epitopes and IgG subclasses could explain the difference [46]. A subsequent investigation of 4G8 and 6E10 glycosylation showed that 4G8 and human anti-Aβ IgG exhibited surface accessible sialic acid groups that could be removed with neuraminidase [47]. By contrast, surface sialic acid was largely absent from 6E10 [47].…”

Section: Introductionmentioning

confidence: 99%

“…A subsequent investigation of 4G8 and 6E10 glycosylation showed that 4G8 and human anti-Aβ IgG exhibited surface accessible sialic acid groups that could be removed with neuraminidase [47]. By contrast, surface sialic acid was largely absent from 6E10 [47]. Taken together, these studies suggested that surface-accessible sialic acid could play a role in BBB transport kinetics.…”

Section: Introductionmentioning

confidence: 99%

“…This in vitro method enables the two opposing processes of influx and efflux to be studied specifically for BBB ECs, facilitating direct measurement of the Permeability Coefficient in each direction. The mAb 4G8 provides a useful model of IgG surface glycans because it exhibits a single, highly processed, surface-accessible N-linked glycan in the Fab light chain [47]. While interpretation of complex glycoproteins can be problematic, the use of 4G8 in the present study enables the effect of a single surface glycan to be studied.…”

Section: Introductionmentioning

confidence: 99%

“…While interpretation of complex glycoproteins can be problematic, the use of 4G8 in the present study enables the effect of a single surface glycan to be studied. For reference, mAb 6E10 is used for comparison as it does not exhibit any detectable surface sialic acid and is also reported to have minimal sialic acid at the Fc glycan [47, 48]. …”

Section: Introductionmentioning

confidence: 99%

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Antibody blood-brain barrier efflux is modulated by glycan modification

Finke

Ayres

Brisbin

et al. 2017

Biochimica et Biophysica Acta (BBA) - General Subjects

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BACKGROUND Drug delivery to the brain is a major roadblock to treatment of Alzheimer’s Disease. Recent results of the PRIME study indicate that increasing brain penetration of antibody drugs improves Alzheimer’s treatment outcomes. New approaches are needed to better accomplish this goal. Based on prior evidence, the hypothesis that glycan modification alters antibody blood-brain barrier permeability was tested here. METHODS The blood-brain barrier permeability coefficient Pe of different glycosylated states of anti-amyloid IgG was measured using in vitro models of brain microvascular endothelial cells. Monoclonal antibodies 4G8, with sialic acid, and 6E10, lacking sialic acid, were studied. The amount of sialic acid was determined using quantitative and semi-quantitative surface plasmon resonance methods. RESULTS Influx of IgG was not saturable and was largely insensitive to IgG species and glycosylation state. By contrast, efflux of 4G8 efflux was significantly lower than both albumin controls and 6E10. Removal of α2,6-linked sialic acid group present on 12% of 4G8 completely restored efflux to that of 6E10 but increasing the α2,6-sialylated fraction to 15% resulted in no change. Removal of the Fc glycan from 4G8 partially restored efflux. Alternate sialic acid groups with α2,3 and α2,8 linkages, nor on the Fc glycan, were not detected at significant levels on either 4G8 or 6E10. CONCLUSIONS These results support a model in which surface-sialylated 4G8 inhibits its own efflux and that of asialylated 4G8. GENERAL SIGNIFICANCE Glycan modification has the potential to increase antibody drug penetration into the brain through efflux inhibition.

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Solution‐Based Determination of Dissociation Constants for the Binding of Aβ42 to Antibodies

2019

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Amyloid β‐peptides (Aβ) play a major role in the pathogenesis of Alzheimer's disease. Therefore, numerous monoclonal antibodies against Aβ have been developed for basic and clinical research. The present study applied fluorescence based analytical ultracentrifugation and microscale thermophoresis to characterize the interaction between Aβ42 monomers and three popular, commercially available antibodies, namely 6E10, 4G8 and 12F4. Both methods allowed us to analyze the interactions at low nanomolar concentrations of analytes close to their dissociation constants ( K D ) as required for the study of high affinity interactions. Furthermore, the low concentrations minimized the unwanted self‐aggregation of Aβ. Our study demonstrates that all three antibodies bind to Aβ42 monomers with comparable affinities in the low nanomolar range. K D values for Aβ42 binding to 6E10 and 4G8 are in good agreement with formerly reported values from SPR studies, while the K D for 12F4 binding to Aβ42 monomer is reported for the first time.

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Anti-Aβ Oligomer IgG and Surface Sialic Acid in Intravenous Immunoglobulin: Measurement and Correlation with Clinical Outcomes in Alzheimer’s Disease Treatment

Cited by 12 publications

References 66 publications

Kinetic analysis of IgG antibodies to beta-amyloid oligomers with surface plasmon resonance

Kinetic analysis of IgG antibodies to beta-amyloid oligomers with surface plasmon resonance

Antibody blood-brain barrier efflux is modulated by glycan modification

Solution‐Based Determination of Dissociation Constants for the Binding of Aβ42 to Antibodies

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