The central nervous system has been considered off-limits to antibody therapeutics. other central nervous system Fas C- Terminal Tripeptide 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. Electronic supplementary Fas C- Terminal Tripeptide material The online version of this article (doi:10.1007/s13311-013-0187-4) contains supplementary material which is available to authorized users. Rabbit Polyclonal to PPP2R5D. IC50s ~15nM) very high doses of drug were needed to substantially inhibit BACE1 activity. Third there is a direct steady-state relationship between drug levels in brain versus drug levels in blood at multiple dose levels equalling approximately 1 to 1000 as reported previously [21 22 Ultimately these findings lead to the conclusion that most antibodies targeting CNS targets could potentially benefit from improved CNS uptake and/or extremely high affinities against that selected target in order to advance toward clinical applications. Removing Amyloid Via Anti-Aβ Treatment Numerous reviews have addressed the immunotherapeutic approaches to target Aβ [4 34 55 thus we will focus on the debate around the mechanism(s) of anti-Aβ action (Fig.?2b) and the most recent clinical advances. From the earliest observations that active immunization against Aβ in APP transgenic mice could reduce plaque load  to the most current clinical data showing that peripheral levels of Aβ increase after dosing and that plaque can be reduced in patients treated with Aβ immunotherapy [59-62] the mechanism by which anti-Aβ antibodies exert their effects have remained somewhat controversial. Based on early publications in the anti-Aβ field two opposing but not mutually exclusive mechanisms have been proposed namely “direct action” and “peripheral sink” (Fig.?2b) [30 63 In the strictest sense of the definition the “peripheral sink” hypothesis stipulates that Aβ captured by anti-Aβ antibodies in the periphery (blood) would shift the equilibrium and “pull” Aβ from the brain into the blood in Fas C- Terminal Tripeptide an attempt Fas C- Terminal Tripeptide to re-establish Aβ equilibrium. This hypothesis relies on the assumption that antibodies do not cross the BBB and that Aβ exists in a passive equilibrium between the brain and blood. Addressing the latter point: if Aβ were to exist in peripheral/central equilibrium any approach that lowers Aβ in the periphery should subsequently reduce brain Aβ levels. Unfortunately the BBB is not a generally permeable barrier and many examples abound where peripheral decreases in Aβ do not result in brain levels being decreased particularly associated with efforts to develop secretase inhibitors . Indeed as just reviewed anti-BACE1 antibodies that inhibit BACE1 Fas C- Terminal Tripeptide activity in the periphery do not show the same reduction of Aβ in brain. Rather the reduction in brain is related to the amount of anti-BACE1 that crosses the BBB . Finally preclinical experiments have been conducted to directly test the idea that peripherally administered anti-Aβ antibodies pull Aβ from brain . Results from these studies suggested the opposite: anti-Aβ/Aβ complexes actually are cleared more slowly from the brain and provide additional proof that anti-Aβ antibodies may be exerting their effects centrally in the CNS. Support is mounting for a “direct action” hypothesis by which anti-Aβ reduce plaque load inhibit aggregation promote disaggregation and possibly directly block the toxicity of oligomeric Aβ (Fig.?2b). This hypothesis stipulates that.