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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

Surface sialic acid is similar between IVIG products and but varies in anti-Aβ monoclonal antibodies.Measurement of the SNA-binding fraction (FSNA+IgG) and ECL-binding fraction (FECL+IgG) in Octagam IVIG (OCT), Gammagard IVIG (GG), mAb 6E10, and mAb 4G8 using CFCA (A) and the On-Chip method (B,C). Two different lots of mAb 4G8 are shown as 4G8a and 4G8b. Each IgG was enzymatically untreated (black bars), 2,6 sialyltransferase treated (2,6ST, light grey bars), and neuraminidase treated (NEU, dark grey bars). Error bars indicate standard deviations (n = 2). CFCA measurements of [IgG]FC_SNA did not meet either the QC or SE criteria and FSNA+IgG and are reported as zero (indicated with asterisk *). Statistical significant differences below p < 0.14 are shown for relevant comparisons, i.e. betweendifferent treatments of the same IgG and between different IgGs with the same enzymatic treatment condition. With the exception of On-Chip SNA/ECL analysis of 6E10 (**, 0.13 < p < 0.19) and On-Chip ECL analysis of GG (***, 0.11 < p <0.13), all NEU-treated IgG differed significantly (p < 0.08) from their corresponding untreated and 2,6ST-treated forms. Other relevant statistically significant differences are indicated as follows: (a) 0.05 < p < 0.10 between untreated 6E10 and 4G8a; (b) 0.02 < p < 0.08 between 2,6ST-treated 6E10 and 4G8b; (c) 0.04 < p < 0.08 between untreated 4G8a and 4G8b; (d) 0.05 < p < 0.11 between 2,6ST-treated 4G8a and p < 0.04 between 2,6ST-treated 4G8b; (e) 0.10 < p < 0.13 between 2,6ST-treated 4G8a and untreated 4G8b; (f) 0.01 < p < 0.03 between 2,6ST-treated 4G8b; (g) 0.08 < p < 0.10 between 2,6ST-treated 4G8b; (h) p < 0.05 between untreated 6E10 and 0.10 < p < 0.13 between untreated 4G8b; (i) p < 0.003 between 2,6ST-treated 4G8b; (j) p = 0.10 between 2,6ST-treated OCT; (k) 0.07 < p 0.11 between NEU-treated 6E10, 4G8a, and 4G8b; (l) 0.06 < p < 0.08 between NEU-treated 6E10, 4G8a, and 4G8b; (m) 0.06 < p 0.08 between NEU-treated 4G8a and 4G8b; (n) p = 0.13 between NEU-treated 4G8b. Differences with p > 0.14 are not shown.
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pone.0120420.g004: Surface sialic acid is similar between IVIG products and but varies in anti-Aβ monoclonal antibodies.Measurement of the SNA-binding fraction (FSNA+IgG) and ECL-binding fraction (FECL+IgG) in Octagam IVIG (OCT), Gammagard IVIG (GG), mAb 6E10, and mAb 4G8 using CFCA (A) and the On-Chip method (B,C). Two different lots of mAb 4G8 are shown as 4G8a and 4G8b. Each IgG was enzymatically untreated (black bars), 2,6 sialyltransferase treated (2,6ST, light grey bars), and neuraminidase treated (NEU, dark grey bars). Error bars indicate standard deviations (n = 2). CFCA measurements of [IgG]FC_SNA did not meet either the QC or SE criteria and FSNA+IgG and are reported as zero (indicated with asterisk *). Statistical significant differences below p < 0.14 are shown for relevant comparisons, i.e. betweendifferent treatments of the same IgG and between different IgGs with the same enzymatic treatment condition. With the exception of On-Chip SNA/ECL analysis of 6E10 (**, 0.13 < p < 0.19) and On-Chip ECL analysis of GG (***, 0.11 < p <0.13), all NEU-treated IgG differed significantly (p < 0.08) from their corresponding untreated and 2,6ST-treated forms. Other relevant statistically significant differences are indicated as follows: (a) 0.05 < p < 0.10 between untreated 6E10 and 4G8a; (b) 0.02 < p < 0.08 between 2,6ST-treated 6E10 and 4G8b; (c) 0.04 < p < 0.08 between untreated 4G8a and 4G8b; (d) 0.05 < p < 0.11 between 2,6ST-treated 4G8a and p < 0.04 between 2,6ST-treated 4G8b; (e) 0.10 < p < 0.13 between 2,6ST-treated 4G8a and untreated 4G8b; (f) 0.01 < p < 0.03 between 2,6ST-treated 4G8b; (g) 0.08 < p < 0.10 between 2,6ST-treated 4G8b; (h) p < 0.05 between untreated 6E10 and 0.10 < p < 0.13 between untreated 4G8b; (i) p < 0.003 between 2,6ST-treated 4G8b; (j) p = 0.10 between 2,6ST-treated OCT; (k) 0.07 < p 0.11 between NEU-treated 6E10, 4G8a, and 4G8b; (l) 0.06 < p < 0.08 between NEU-treated 6E10, 4G8a, and 4G8b; (m) 0.06 < p 0.08 between NEU-treated 4G8a and 4G8b; (n) p = 0.13 between NEU-treated 4G8b. Differences with p > 0.14 are not shown.

Mentions: Fig 4 shows a comparison of the fraction of SNA-binding and ECL-binding IgG in IVIG and of mAbs 6E10 and 4G8. In addition, the values of FSNA+IgG and FECL+IgG are determined in untreated IgG products after treatment with 2,6 sialyltransferase (2,6ST) and after treatment with neuraminidase (NEU). Fig 4A and 4B show values of FSNA+IgG, determined by CFCA and the On-Chip method respectively. Fig 4C confirms these findings with values of FECL+IgG determined by the On-Chip method. Due to a high variability noted for FSNA+IgG and FECL+IgG between lots of mAb 4G8, the individual 4G8 lot values are shown as 4G8a and 4G8b.


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)

Surface sialic acid is similar between IVIG products and but varies in anti-Aβ monoclonal antibodies.Measurement of the SNA-binding fraction (FSNA+IgG) and ECL-binding fraction (FECL+IgG) in Octagam IVIG (OCT), Gammagard IVIG (GG), mAb 6E10, and mAb 4G8 using CFCA (A) and the On-Chip method (B,C). Two different lots of mAb 4G8 are shown as 4G8a and 4G8b. Each IgG was enzymatically untreated (black bars), 2,6 sialyltransferase treated (2,6ST, light grey bars), and neuraminidase treated (NEU, dark grey bars). Error bars indicate standard deviations (n = 2). CFCA measurements of [IgG]FC_SNA did not meet either the QC or SE criteria and FSNA+IgG and are reported as zero (indicated with asterisk *). Statistical significant differences below p < 0.14 are shown for relevant comparisons, i.e. betweendifferent treatments of the same IgG and between different IgGs with the same enzymatic treatment condition. With the exception of On-Chip SNA/ECL analysis of 6E10 (**, 0.13 < p < 0.19) and On-Chip ECL analysis of GG (***, 0.11 < p <0.13), all NEU-treated IgG differed significantly (p < 0.08) from their corresponding untreated and 2,6ST-treated forms. Other relevant statistically significant differences are indicated as follows: (a) 0.05 < p < 0.10 between untreated 6E10 and 4G8a; (b) 0.02 < p < 0.08 between 2,6ST-treated 6E10 and 4G8b; (c) 0.04 < p < 0.08 between untreated 4G8a and 4G8b; (d) 0.05 < p < 0.11 between 2,6ST-treated 4G8a and p < 0.04 between 2,6ST-treated 4G8b; (e) 0.10 < p < 0.13 between 2,6ST-treated 4G8a and untreated 4G8b; (f) 0.01 < p < 0.03 between 2,6ST-treated 4G8b; (g) 0.08 < p < 0.10 between 2,6ST-treated 4G8b; (h) p < 0.05 between untreated 6E10 and 0.10 < p < 0.13 between untreated 4G8b; (i) p < 0.003 between 2,6ST-treated 4G8b; (j) p = 0.10 between 2,6ST-treated OCT; (k) 0.07 < p 0.11 between NEU-treated 6E10, 4G8a, and 4G8b; (l) 0.06 < p < 0.08 between NEU-treated 6E10, 4G8a, and 4G8b; (m) 0.06 < p 0.08 between NEU-treated 4G8a and 4G8b; (n) p = 0.13 between NEU-treated 4G8b. Differences with p > 0.14 are not shown.
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Related In: Results  -  Collection

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Show All Figures
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pone.0120420.g004: Surface sialic acid is similar between IVIG products and but varies in anti-Aβ monoclonal antibodies.Measurement of the SNA-binding fraction (FSNA+IgG) and ECL-binding fraction (FECL+IgG) in Octagam IVIG (OCT), Gammagard IVIG (GG), mAb 6E10, and mAb 4G8 using CFCA (A) and the On-Chip method (B,C). Two different lots of mAb 4G8 are shown as 4G8a and 4G8b. Each IgG was enzymatically untreated (black bars), 2,6 sialyltransferase treated (2,6ST, light grey bars), and neuraminidase treated (NEU, dark grey bars). Error bars indicate standard deviations (n = 2). CFCA measurements of [IgG]FC_SNA did not meet either the QC or SE criteria and FSNA+IgG and are reported as zero (indicated with asterisk *). Statistical significant differences below p < 0.14 are shown for relevant comparisons, i.e. betweendifferent treatments of the same IgG and between different IgGs with the same enzymatic treatment condition. With the exception of On-Chip SNA/ECL analysis of 6E10 (**, 0.13 < p < 0.19) and On-Chip ECL analysis of GG (***, 0.11 < p <0.13), all NEU-treated IgG differed significantly (p < 0.08) from their corresponding untreated and 2,6ST-treated forms. Other relevant statistically significant differences are indicated as follows: (a) 0.05 < p < 0.10 between untreated 6E10 and 4G8a; (b) 0.02 < p < 0.08 between 2,6ST-treated 6E10 and 4G8b; (c) 0.04 < p < 0.08 between untreated 4G8a and 4G8b; (d) 0.05 < p < 0.11 between 2,6ST-treated 4G8a and p < 0.04 between 2,6ST-treated 4G8b; (e) 0.10 < p < 0.13 between 2,6ST-treated 4G8a and untreated 4G8b; (f) 0.01 < p < 0.03 between 2,6ST-treated 4G8b; (g) 0.08 < p < 0.10 between 2,6ST-treated 4G8b; (h) p < 0.05 between untreated 6E10 and 0.10 < p < 0.13 between untreated 4G8b; (i) p < 0.003 between 2,6ST-treated 4G8b; (j) p = 0.10 between 2,6ST-treated OCT; (k) 0.07 < p 0.11 between NEU-treated 6E10, 4G8a, and 4G8b; (l) 0.06 < p < 0.08 between NEU-treated 6E10, 4G8a, and 4G8b; (m) 0.06 < p 0.08 between NEU-treated 4G8a and 4G8b; (n) p = 0.13 between NEU-treated 4G8b. Differences with p > 0.14 are not shown.
Mentions: Fig 4 shows a comparison of the fraction of SNA-binding and ECL-binding IgG in IVIG and of mAbs 6E10 and 4G8. In addition, the values of FSNA+IgG and FECL+IgG are determined in untreated IgG products after treatment with 2,6 sialyltransferase (2,6ST) and after treatment with neuraminidase (NEU). Fig 4A and 4B show values of FSNA+IgG, determined by CFCA and the On-Chip method respectively. Fig 4C confirms these findings with values of FECL+IgG determined by the On-Chip method. Due to a high variability noted for FSNA+IgG and FECL+IgG between lots of mAb 4G8, the individual 4G8 lot values are shown as 4G8a and 4G8b.

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