Clinical development of passive tau-based immunotherapeutics for treating primary and secondary tauopathies.

INTRODUCTION: Tauopathies are clinicopathological entities with increased and pathological deposition in glia and/or neurons of hyperphosphorylated aggregates of the microtubule-binding protein tau. In secondary tauopathies, i.e. Alzheimer's disease (AD), tau deposition can be observed, but tau coexists with another protein (amyloid-ß). In the last 20 years, little progress has been made in developing disease-modifying drugs for primary and secondary tauopathies and available symptomatic drugs have limited efficacy. AREAS COVERED: The present review summarized recent advances about the development and challenges in treatments for primary and secondary tauopathies, with a focus on passive tau-based immunotherapy. EXPERT OPINION: Several tau-targeted passive immunotherapeutics are in development for treating tauopathies. At present, 14 anti-tau antibodies have entered clinical trials, and 9 of them are still in clinical testing for progressive supranuclear palsy syndrome and AD (semorinemab, bepranemab, E2814, JNJ-63733657, Lu AF87908, APNmAb005, MK-2214, PNT00, and PRX005). However, none of these nine agents have reached Phase III. The most advanced anti-tau monoclonal antibody for treating AD is semorinemab, while bepranemab is the only anti-tau monoclonal antibody still in clinical testing for treating progressive supranuclear palsy syndrome. Further evidence on passive immunotherapeutics for treating primary and secondary tauopathies will come from ongoing Phase I/II trials.

Characterisation of medical microfluidic systems regarding fast changing flow rates using optical front tracking methods.

The presented optical flow metering methods are appropriate to characterise the dynamic properties of microfluidic systems. The dynamic behaviour of clinical or medical devices, micro pumps and flow sensors based on thermal methods were investigated. The Camera-System covers a flow range from 50nl/min to 500µl/min. The uncertainty is less than 4%, sample rates up to 5kS/s. The Displacement-Sensor-System covers a flow range between 100µl/min and 50ml/min. The uncertainty is less than 3% at sample rates up to 49kS/s. It was shown that measuring pulsating flow rates with thermal flow sensors is possible, but the signal is low pass filtered. The low pass behaviour is determined by the thermal properties, thermal resistance and heat capacity, of the flow channel. But the mean flow rate was always measured properly. The fluidic properties of two different types of micro pumps were examined and characterised exemplary.

An experimental setup for traceable measurement and calibration of liquid flow rates down to 5 nl/min.

This work presents the improvements of an experimental setup for measuring ultra-low flow rates down to 5 nl/min. The system uses a telecentric CCD imaging system mounted on a high-precision, computer-controlled linear stage to track a moving liquid meniscus inside a glass capillary. Compared to the original setup, the lowest attainable expanded uncertainty at any flow rate has been reduced from 5.4% to 2%. In addition, the conformity with specification of three commercial micro-fluidic devices was evaluated using the new setup: one syringe pump, one implantable infusion pump and one thermal flow sensor. The flow sensor and the implantable infusion pump met the compliance criteria (coverage probability 95%). The syringe pump however, failed to meet the specifications at 5 nl/min and 10 nl/min. No assessment could be made at higher flow rates.