Limits...
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

On-Chip SPR measurement of IgG surface sialic acid.A representative SPR On-Chip experiment of a 66-fold dilution of 4G8a in a flow cell with immobilized OAβ. In Step 1, IgG (4G8a) is bound for 120 s and the association binding signal, RUIgG, is measured. In Step 2, 3 μM SNA lectin is bound for 180 s to the flow cell containing IgG and this second association signal, RUL+IgG, is measured. The background binding signal of 3 μM SNA, RUL-IgG, is measured for the flow cell in the absence of IgG (grey curve/arrow).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4380445&req=5

pone.0120420.g002: On-Chip SPR measurement of IgG surface sialic acid.A representative SPR On-Chip experiment of a 66-fold dilution of 4G8a in a flow cell with immobilized OAβ. In Step 1, IgG (4G8a) is bound for 120 s and the association binding signal, RUIgG, is measured. In Step 2, 3 μM SNA lectin is bound for 180 s to the flow cell containing IgG and this second association signal, RUL+IgG, is measured. The background binding signal of 3 μM SNA, RUL-IgG, is measured for the flow cell in the absence of IgG (grey curve/arrow).

Mentions: As a complementary method to determine FSNA+ IgG, an ELISA-based “On-Chip” technique was also used to determine FSNA+ IgG. The On-Chip method was also used to determine FECL+IgG, the fraction of IgG that bound ECL, a lectin specific to terminal galactose residues with an α1,4 linkage to a preceding N-aceytylglucosamine [55]. The On-Chip method involves an initial binding step of IgG followed with a second binding step with excess SNA (3 μM) or excess ECL (33 μM). A representative example of FSNA+IgG measurement of 4G8a in the OAβ flow cell is shown in Fig 2. All On-Chip FSNA+ IgG measurements for 6E10 and 4G8 were performed using the OAβ flow cell. For IVIG, the SpA flow cell was used to determine FSNA+ IgG for total IVIG and the OAβ flow cell was used to determine FSNA+ IgG of the OAβ+ IgG subgroup.


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)

On-Chip SPR measurement of IgG surface sialic acid.A representative SPR On-Chip experiment of a 66-fold dilution of 4G8a in a flow cell with immobilized OAβ. In Step 1, IgG (4G8a) is bound for 120 s and the association binding signal, RUIgG, is measured. In Step 2, 3 μM SNA lectin is bound for 180 s to the flow cell containing IgG and this second association signal, RUL+IgG, is measured. The background binding signal of 3 μM SNA, RUL-IgG, is measured for the flow cell in the absence of IgG (grey curve/arrow).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0120420.g002: On-Chip SPR measurement of IgG surface sialic acid.A representative SPR On-Chip experiment of a 66-fold dilution of 4G8a in a flow cell with immobilized OAβ. In Step 1, IgG (4G8a) is bound for 120 s and the association binding signal, RUIgG, is measured. In Step 2, 3 μM SNA lectin is bound for 180 s to the flow cell containing IgG and this second association signal, RUL+IgG, is measured. The background binding signal of 3 μM SNA, RUL-IgG, is measured for the flow cell in the absence of IgG (grey curve/arrow).
Mentions: As a complementary method to determine FSNA+ IgG, an ELISA-based “On-Chip” technique was also used to determine FSNA+ IgG. The On-Chip method was also used to determine FECL+IgG, the fraction of IgG that bound ECL, a lectin specific to terminal galactose residues with an α1,4 linkage to a preceding N-aceytylglucosamine [55]. The On-Chip method involves an initial binding step of IgG followed with a second binding step with excess SNA (3 μM) or excess ECL (33 μM). A representative example of FSNA+IgG measurement of 4G8a in the OAβ flow cell is shown in Fig 2. All On-Chip FSNA+ IgG measurements for 6E10 and 4G8 were performed using the OAβ flow cell. For IVIG, the SpA flow cell was used to determine FSNA+ IgG for total IVIG and the OAβ flow cell was used to determine FSNA+ IgG of the OAβ+ IgG subgroup.

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