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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.

Kwon H, Crisostomo AC, Smalls HM, Finke JM - PLoS ONE (2015)

Bottom Line: The fraction of IgG antibodies with anti-oligomeric Aβ affinity and surface sialic acid was compared between Octagam and Gammagard intravenous immunoglobulin (IVIG) using two complementary surface plasmon resonance methods.The fraction and location of surface-accessible sialic acid in the Fab domain was found to be similar between Gammagard and Octagam.These findings indicate that anti-oligomeric Aβ IgG and total surface sialic acid alone cannot account for reported clinical differences in the two IVIG products.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicinal Chemistry, University of Washington, Seattle, Washington, United States of America.

ABSTRACT
The fraction of IgG antibodies with anti-oligomeric Aβ affinity and surface sialic acid was compared between Octagam and Gammagard intravenous immunoglobulin (IVIG) using two complementary surface plasmon resonance methods. These comparisons were performed to identify if an elevated fraction existed in Gammagard, which reported small putative benefits in a recent Phase III clinical trial for Alzheimer's Disease. The fraction of anti-oligomeric Aβ IgG was found to be higher in Octagam, for which no cognitive benefits were reported. The fraction and location of surface-accessible sialic acid in the Fab domain was found to be similar between Gammagard and Octagam. These findings indicate that anti-oligomeric Aβ IgG and total surface sialic acid alone cannot account for reported clinical differences in the two IVIG products. A combined analysis of sialic acid in anti-oligomeric Aβ IgG did reveal a notable finding that this subgroup exhibited a high degree of surface sialic acid lacking the conventional α2,6 linkage. These results demonstrate that the IVIG antibodies used to engage oligomeric Aβ in both Gammagard and Octagam clinical trials did not possess α2,6-linked surface sialic acid at the time of administration. Anti-oligomeric Aβ IgG with α2,6 linkages remains untested as an AD treatment.

No MeSH data available.


Related in: MedlinePlus

CFCA measurements of IgG subgroups with high ligand affinity.CFCA raw SPR data and fits of 4G8a association using a 833-fold stock dilution in a flow cell with immobilized SNA lectin (A) and a 3333-fold stock dilution in a flow cell with immobilized OAβ (B). The raw data and fits at flow rates 5 μl/min and 100 μl/min are indicated along with the QC parameter and percent standard error SE of the CFCA fit. The concentration of the original 4G8a stock determined from UV measurements was 6500 nM.
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pone.0120420.g001: CFCA measurements of IgG subgroups with high ligand affinity.CFCA raw SPR data and fits of 4G8a association using a 833-fold stock dilution in a flow cell with immobilized SNA lectin (A) and a 3333-fold stock dilution in a flow cell with immobilized OAβ (B). The raw data and fits at flow rates 5 μl/min and 100 μl/min are indicated along with the QC parameter and percent standard error SE of the CFCA fit. The concentration of the original 4G8a stock determined from UV measurements was 6500 nM.

Mentions: CFCA was performed using two sequential injections of IgG at different flow rates, 5 and 100 μl/min, and the association slope measured for 30 s under each flow rate. In general, only the middle time points of association period (5–25 s) were used in determining the slope to avoid signal artifacts at the start and end of the injection period. Representative CFCA measurements and fitted linear slopes are shown for mAb 4G8a on the SNA sensor chip (Fig 1A) and on the OAβ sensor chip (Fig 1B).


Anti-aβ oligomer IgG and surface sialic acid in intravenous immunoglobulin: measurement and correlation with clinical outcomes in Alzheimer's disease treatment.

Kwon H, Crisostomo AC, Smalls HM, Finke JM - PLoS ONE (2015)

CFCA measurements of IgG subgroups with high ligand affinity.CFCA raw SPR data and fits of 4G8a association using a 833-fold stock dilution in a flow cell with immobilized SNA lectin (A) and a 3333-fold stock dilution in a flow cell with immobilized OAβ (B). The raw data and fits at flow rates 5 μl/min and 100 μl/min are indicated along with the QC parameter and percent standard error SE of the CFCA fit. The concentration of the original 4G8a stock determined from UV measurements was 6500 nM.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4380445&req=5

pone.0120420.g001: CFCA measurements of IgG subgroups with high ligand affinity.CFCA raw SPR data and fits of 4G8a association using a 833-fold stock dilution in a flow cell with immobilized SNA lectin (A) and a 3333-fold stock dilution in a flow cell with immobilized OAβ (B). The raw data and fits at flow rates 5 μl/min and 100 μl/min are indicated along with the QC parameter and percent standard error SE of the CFCA fit. The concentration of the original 4G8a stock determined from UV measurements was 6500 nM.
Mentions: CFCA was performed using two sequential injections of IgG at different flow rates, 5 and 100 μl/min, and the association slope measured for 30 s under each flow rate. In general, only the middle time points of association period (5–25 s) were used in determining the slope to avoid signal artifacts at the start and end of the injection period. Representative CFCA measurements and fitted linear slopes are shown for mAb 4G8a on the SNA sensor chip (Fig 1A) and on the OAβ sensor chip (Fig 1B).

Bottom Line: The fraction of IgG antibodies with anti-oligomeric Aβ affinity and surface sialic acid was compared between Octagam and Gammagard intravenous immunoglobulin (IVIG) using two complementary surface plasmon resonance methods.The fraction and location of surface-accessible sialic acid in the Fab domain was found to be similar between Gammagard and Octagam.These findings indicate that anti-oligomeric Aβ IgG and total surface sialic acid alone cannot account for reported clinical differences in the two IVIG products.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicinal Chemistry, University of Washington, Seattle, Washington, United States of America.

ABSTRACT
The fraction of IgG antibodies with anti-oligomeric Aβ affinity and surface sialic acid was compared between Octagam and Gammagard intravenous immunoglobulin (IVIG) using two complementary surface plasmon resonance methods. These comparisons were performed to identify if an elevated fraction existed in Gammagard, which reported small putative benefits in a recent Phase III clinical trial for Alzheimer's Disease. The fraction of anti-oligomeric Aβ IgG was found to be higher in Octagam, for which no cognitive benefits were reported. The fraction and location of surface-accessible sialic acid in the Fab domain was found to be similar between Gammagard and Octagam. These findings indicate that anti-oligomeric Aβ IgG and total surface sialic acid alone cannot account for reported clinical differences in the two IVIG products. A combined analysis of sialic acid in anti-oligomeric Aβ IgG did reveal a notable finding that this subgroup exhibited a high degree of surface sialic acid lacking the conventional α2,6 linkage. These results demonstrate that the IVIG antibodies used to engage oligomeric Aβ in both Gammagard and Octagam clinical trials did not possess α2,6-linked surface sialic acid at the time of administration. Anti-oligomeric Aβ IgG with α2,6 linkages remains untested as an AD treatment.

No MeSH data available.


Related in: MedlinePlus