Protein size and cerebrospinal fluid composition

Felgenhauer, K.

doi:10.1007/bf01466734

Cited by 372 publications

(196 citation statements)

References 35 publications

Supporting

Mentioning

178

Contrasting

Unclassified

Order By: Relevance

“…In general, only a mere 0.1-0.2 % of circulating antibodies cross the BBB and enter the brain or CSF [21,22]. This uptake is similar in magnitude to other endogenous circulating proteins that are taken up into brain in a nonspecific Receptor-mediated transport relies on substrate-specific binding of antibodies to endocytic receptors expressed on the luminal surface of endothelial cells.…”

Section: Limited Quantities Of Therapeutic Antibodies Cross the Bbbmentioning

confidence: 99%

Developing Therapeutic Antibodies for Neurodegenerative Disease

Yu¹,

Watts²

2013

Neurotherapeutics

176

171

View full text Add to dashboard Cite

The central nervous system has been considered off-limits to antibody therapeutics. However, recent advances in preclinical and clinical drug development suggest that antibodies can cross the blood-brain barrier in limited quantities and act centrally to mediate their effects. In particular, immunotherapy for Alzheimer's disease has shown that targeting beta amyloid with antibodies can reduce pathology in both mouse models and the human brain, with strong evidence supporting a central mechanism of action. These findings have fueled substantial efforts to raise antibodies against other central nervous system targets, particularly neurodegenerative targets, such as tau, beta-secretase, and alpha-synuclein. Nevertheless, it is also apparent that antibody penetration across the blood-brain barrier is limited, with an estimated 0.1-0.2 % of circulating antibodies found in brain at steady-state concentrations. Thus, technologies designed to improve antibody uptake in brain are receiving increased attention and are likely going to represent the future of antibody therapy for neurologic diseases, if proven safe and effective. Herein we review briefly the progress and limitations of traditional antibody drug development for neurodegenerative diseases, with a focus on passive immunotherapy. We also take a more in-depth look at new technologies for improved delivery of antibodies to the brain.

show abstract

Section: Limited Quantities Of Therapeutic Antibodies Cross the Bbbmentioning

confidence: 99%

Developing Therapeutic Antibodies for Neurodegenerative Disease

Yu¹,

Watts²

2013

Neurotherapeutics

176

171

View full text Add to dashboard Cite

show abstract

“…These data are taken from the following sources: for P 1,0 we refer to Guyton et al (1996), for P 2,0 to Felgenhauer (1974), R 2,0 is a typical value for a low receptor concentration, and for L 2,0 we refer to Rouser et al (1968). In our simulations we assume that there are no lipids or receptors in the plasma compartment.…”

Section: The Basic Modelmentioning

confidence: 99%

Impact of protein binding on receptor occupancy: A two-compartment model

Peletier

Benson

Graaf

2010

Journal of Theoretical Biology

View full text Add to dashboard Cite

In this paper we analyse the impact of protein-and lipid-and receptor-binding on receptor occupancy in a two-compartment system, with proteins in both compartments and lipids and receptors in the peripheral compartment only. We do this for two manners of drug administration: a bolus administration and a constant rate infusion, both into the central compartment. We derive explicit approximations for the timecurves of the different compounds valid for a wide range of realistic values of rate constants and initial concentrations of proteins, lipids, receptors and the drug. These approximations are used to obtain both qualitative and quantitative insight into such critical properties as the distribution of the drug over the two compartments, the maximum receptor occupancy and the area under the drug-receptor complex curve. In particular we focus on assessing the impact of the dissociation constants, K P , K L and K R of the drug with, respectively, the proteins, the lipids and the receptors, the permeability and the surface area of the membrane between compartments, and the rate the drug is eliminated from the system.

show abstract

“…However, cerebrospinal fluid (CSF) contains a tiny concentration of blood‐borne Igs reflecting a low‐rate passive diffusion of molecules through the blood–CSF barrier (BCB) to the CSF. It has long been known that although virtually all molecules may diffuse from serum to the CSF, the permeability of the BCB positively correlates with their molecular weight 1. For example, the ratio increases from 1:205 with albumin (65 kDa) to 1:440 with IgG (150 kDa) and 1:900 with IgM (970 kDa) 2.…”

Section: Introductionmentioning

confidence: 99%

Estimation of intrathecal IgG synthesis: simulation of the risk of underestimation

Bonnan

Gianoli-Guillerme

Courtade

et al. 2018

Ann Clin Transl Neurol

View full text Add to dashboard Cite

ObjectiveThe low level of passively diffused IgG through the blood–brain barrier is sufficient to blur the estimation of intrathecal IgG synthesis (ITS). Therefore, this estimation requires a mathematical calculation derived from empirical laws, but the range of normal values in healthy controls is wide enough to prevent a precise calculation. This study investigated the precision of various methods of ITS estimations and their application to two clinical situations: plasma exchange and immune suppression targeting ITS.MethodsBased on a mathematical model of ITS, we constructed a population of healthy controls and applied a tunable ITS.ResultsWe demonstrate the following results: underestimation of ITS is common at individual level but true ITS is well fitted by cohorts; Q IgG increases after plasma exchange; IgG Loc calculation based on Qlim falsely increases when Q Alb decreases; the sample size required to demonstrate a decrease in ITS increases exponentially with larger Q Alb.InterpretationStudies evaluating changes in ITS level should be adjusted to Q Alb. Low amounts of ITS could be largely underestimated.

show abstract

Protein size and cerebrospinal fluid composition

Cited by 372 publications

References 35 publications

Developing Therapeutic Antibodies for Neurodegenerative Disease

Developing Therapeutic Antibodies for Neurodegenerative Disease

Impact of protein binding on receptor occupancy: A two-compartment model

Estimation of intrathecal IgG synthesis: simulation of the risk of underestimation

Contact Info

Product

Resources

About