Brain Bioavailability of Human Intravenous Immunoglobulin and its Transport through the Murine Blood–Brain Barrier

Abstract

Intravenous immunoglobulin (IVIg) is currently evaluated in clinical trials for the treatment of various disorders of the central nervous system. To assess its capacity to reach central therapeutic targets, the brain bioavailability of IVIg must be determined. We thus quantified the passage of IVIg through the blood-brain barrier (BBB) of C57Bl/6 mice using complementary quantitative and qualitative methodologies. As determined by enzyme-linked immunosorbent assay, a small proportion of systemically injected IVIg was detected in the brain of mice (0.009 ± 0.001% of injected dose in the cortex) whereas immunostaining revealed localization mainly within microvessels and less frequently in neurons. Pharmacokinetic analyses evidenced a low elimination rate constant (0.0053 per hour) in the cortex, consistent with accumulation within cerebral tissue. In situ cerebral perfusion experiments revealed that a fraction of IVIg crossed the BBB without causing leakage. A dose-dependent decrease of brain uptake was consistent with a saturable blood-to-brain transport mechanism. Finally, brain uptake of IVIg after a subchronic treatment was similar in the 3xTg-AD mouse model of Alzheimer disease compared with nontransgenic controls. In summary, our results provide evidence of BBB passage and bioavailability of IVIg into the brain in the absence of BBB leakage and in sufficient concentration to interact with the therapeutic targets.

Human Apolipoprotein E ε4 Expression Impairs Cerebral Vascularization and Blood—Brain Barrier Function in Mice

“…Since hIgG are large molecules, they do not cross the BBB, or only in very small amount (o 0.01% of injected dose). 24 As shown in Figures 4D and 4E, no difference in hIgG concentrations in the hippocampus and the cortex was found between APOE2 and APOE4 mice after three intraperitoneal injections of 30 mg hIgG 96, 24, and 1 hour(s) before killing. These data corroborate [ 14 C]-sucrose data and confirm that no major breakdown of BBB integrity occurred in APOE4 mice.…”

“…The concentration of hIgG in each tissue was determined by specific enzyme-linked immunosorbent assay using hIgG Fc-specific antibodies for capture and the corresponding horseradish peroxidaseconjugated antibodies for detection (Jackson ImmunoResearch Laboratories, West Grove, PA, USA). 24 Figure 2. Relative vessel density in the hippocampus was reduced in APOE4 mice.…”

Amyloid‐β concentration and structure influences the transport and immunomodulatory effects ofIVIG

“…It has previously been shown that human‐derived IVIG is compatible with mouse models and no significant differences between IVIG and mouse IgG treatment groups have been observed (St‐Amour et al . ; Sudduth et al . ).…”

A Popperian View on Anti‐CGRP Biologics in Migraine

“…In this regard, the estimation of the brain concentration of a given receptor is practically impossible, only the antibodies against CGRP will be first considered. 23,30 When translated to CGRP biologics, this indicates that they are 300-fold less concentrated in the brain than in plasma, thereby suggesting that they act outside the BBB. This represents a key functional, protective parameter also in light of the constitutive defect in autoreactive B cell negative selection in humans, and ensuing risk of autoimmune humoral attacks against the brain.…”