P3‐248: Intravenous immunoglobulin (IVIg) Gammagard liquid contains anti‐RAGE IgG and sLRP

Weber, Alfred; Engelmaier, Andrea; Teschner, Wolfgang; Ehrlich, Hartmut J.; Schwarz, Hans

doi:10.1016/j.jalz.2009.04.1021

Cited by 6 publications

(5 citation statements)

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“…RAGE is a therapeutic target of interest in AD because its blockade reduces neuronal and synaptic injury [ 130 ]. The anti-RAGE antibodies reportedly present in IVIG [ 131 ] could block the receptor, reducing the influx of Aβ into the brain, and thereby lowering brain Aβ levels [ 19 ]. It would be appropriate to include these antibodies in AD-specific IVIG.…”

Section: Reviewmentioning

confidence: 99%

Should development of Alzheimer’s disease-specific intravenous immunoglobulin be considered?

Loeffler

2014

J Neuroinflammation

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Recent phase II and III studies with intravenous immunoglobulin (IVIG) in patients with Alzheimer’s disease (AD) did not find evidence for the slowing of AD progression compared to placebo-treated patients, in contrast to encouraging results in pilot studies. An additional phase III trial is ongoing. If negative results are found, then further AD studies with IVIG are unlikely unless a manufacturer opts for a trial with high-dose IVIG, which would increase its anti-inflammatory effects but also the risk for adverse events. An alternative approach could be an AD-specific IVIG, supplementing IVIG with higher concentrations of selected antibodies purified from it or produced via recombinant polyclonal antibody technology. These antibodies could include those to amyloid-beta (Aβ, tau protein, inflammatory cytokines, complement activation proteins, and the receptor for advanced glycation end products. IgG fragment crystallizable (Fc) fragments containing terminal sialic acid could be added to increase anti-inflammatory effects. While this product might be more effective in slowing AD clinical progression than current IVIG, there are difficulties with this approach. Preclinical studies would be required to determine which of the antibodies of interest for supplementing current IVIG (for example, antibodies to phosphorylated or oligomeric tau) are actually present (and, therefore, available for purification) in IVIG, and the effects of the product in mouse models of AD. An Investigational New Drug application for an AD-specific IVIG would require United States Food and Drug Administration approval. If the drug would be found to benefit AD patients, meeting the increased demand for IVIG would be challenging.

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Section: Reviewmentioning

confidence: 99%

Should development of Alzheimer’s disease-specific intravenous immunoglobulin be considered?

Loeffler

2014

J Neuroinflammation

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“…Importantly, recombinant LRP fragments can effectively replace oxidized sLRP and sequester free Ab in plasma in AD patients and AD transgenic mice, ultimately reducing Ab-related pathology in brain . Consistent with these findings, it has been suggested that sLRP and anti-RAGE antibodies that are present in Baxter's intravenous immunoglobulin preparation Gammagard Liquid may contribute to the observed beneficial effects of Gammagard Liquid in AD patients (Relkin et al 2009;Weber et al 2009) by improving the peripheral Ab sequestration and preventing entry of free Ab into the brain (Dodel et al 2010).…”

Section: Lrpmentioning

confidence: 72%

Neurovascular Dysfunction and Faulty Amyloid -Peptide Clearance in Alzheimer Disease

Sagare

Bell

Zloković

2012

Cold Spring Harbor Perspectives in Medicine

215

177

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Neurovascular dysfunction is an integral part of Alzheimer disease (AD). Changes in the brain vascular system may contribute in a significant way to the onset and progression of cognitive decline and the development of a chronic neurodegenerative process associated with accumulation of amyloid b-peptide (Ab) in brain and cerebral vessels in AD individuals and AD animal models. Here, we review the role of the neurovascular unit and molecular mechanisms in cerebral vascular cells behind the pathogenesis of AD. In particular, we focus on blood-brain barrier (BBB) dysfunction, decreased cerebral blood flow, and impaired vascular clearance of Ab from brain. The data reviewed here support an essential role of the neurovascular and BBB mechanisms in AD pathogenesis.

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“…2007a). It is of note, a recent phase II clinical trial in patients with mild AD with Baxter’s intravenous immunoglobulin preparation Gammagard Liquid containing both sLRP1 and anti‐RAGE immunoglobulins (Weber et al. 2009) has shown encouraging results (Relkin et al.…”

Section: Lrp1: a Three‐step Homeostatic Control Of Aβ Clearancementioning

confidence: 99%

Low‐density lipoprotein receptor‐related protein‐1: a serial clearance homeostatic mechanism controlling Alzheimer’s amyloid β‐peptide elimination from the brain

Zloković

Deane

Sagare

et al. 2010

Journal of Neurochemistry

229

176

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Low-density lipoprotein receptor-related protein-1 (LRP1), a member of the low-density lipoprotein receptor family, has major roles in the cellular transport of cholesterol, endocytosis of 40 structurally diverse ligands, transcytosis of ligands across the blood-brain barrier, and transmembrane and nuclear signaling. Recent evidence indicates that LRP1 regulates brain and systemic clearance of Alzheimer's disease (AD) amyloid b-peptide (Ab). According to the two-hit vascular hypothesis for AD, vascular damage precedes cerebrovascular and brain Ab accumulation (hit 1) which then further amplifies neurovascular dysfunction (hit 2) preceding neurodegeneration. In this study, we discuss the roles of LRP1 during the hit 1 and hit 2 stage of AD pathogenesis and describe a three-level serial LRP1-dependent homeostatic control of Ab clearance including (i) cell-surface LRP1 at the blood-brain barrier and cerebrovascular cells mediating brainto-blood Ab clearance (ii) circulating LRP1 providing a key endogenous peripheral 'sink' activity for plasma Ab which prevents free Ab access to the brain, and (iii) LRP1 in the liver mediating systemic Ab clearance. Pitfalls in experimental Ab brain clearance measurements with the concurrent use of peptides/proteins such as receptor-associated protein and aprotinin are also discussed. We suggest that LRP1 has a critical role in AD pathogenesis and is an important therapeutic target in AD.

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P3‐248: Intravenous immunoglobulin (IVIg) Gammagard liquid contains anti‐RAGE IgG and sLRP

Cited by 6 publications

References 0 publications

Should development of Alzheimer’s disease-specific intravenous immunoglobulin be considered?

Should development of Alzheimer’s disease-specific intravenous immunoglobulin be considered?

Neurovascular Dysfunction and Faulty Amyloid -Peptide Clearance in Alzheimer Disease

Low‐density lipoprotein receptor‐related protein‐1: a serial clearance homeostatic mechanism controlling Alzheimer’s amyloid β‐peptide elimination from the brain

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