Ultrasound-mediated delivery of novel tau-specific monoclonal antibody enhances brain uptake but not therapeutic efficacy

Abstract

Tau-specific immunotherapy is an attractive therapeutic strategy for the treatment of Alzheimer's disease and other tauopathies. However, targeting tau effectively remains a considerable challenge due to the restrictive nature of the blood-brain barrier (BBB), which excludes 99.9% of peripherally administered antibodies. We have previously shown that the delivery of tau-specific monoclonal antibody (mAb) with low-intensity scanning ultrasound in combination with intravenously injected microbubbles (SUS+MB) increases the passage of IgG antibodies into the brain. SUS+MB transiently opens tight junctions to allow paracellular transport, but also facilitates transcellular transport, particularly for larger cargoes. However, therapeutic efficacy after enhanced brain delivery has not been explored. To assess whether ultrasound-mediated delivery of tau-specific mAbs leads to an enhanced therapeutic response, K369I tau transgenic K3 mice were passively immunised once weekly for 12 weeks with a novel mAb, RNF5, in combination with SUS+MB. While none of the treatment arms improved behaviour or motor functions in these mice, we found that both RNF5 and SUS+MB treatments on their own reduced tau pathology, but, surprisingly, the combination of both (RNF5+SUS+MB) did not achieve an additive reduction in tau pathology. This was despite observing increased antibody penetration in the brain. Interestingly, a significant fraction of the antibody in the combination treatment was visualized in brain endothelial cells, suggesting that paracellular transport may not be the preferred uptake mechanism for RNF5. Taken altogether, more research is warranted to develop SUS+MB as a delivery modality for anti-tau antibodies.

A sporadic Alzheimer’s blood-brain barrier model for developing ultrasound-mediated delivery of Aducanumab and anti-Tau antibodies

“…The effect of FUS +MB was tested on iBECs 48– 72h after subculture on Transwell inserts. FITC-conjugated dextran (150 kDa) was added at 0.5 mg/ml and AlexaFluor™-647-conjugated anti-amyloid-β (Aducanumab) and anti-Tau (RNF5, [26]) therapeutic antibodies were added at 1 μM. MB (10 μL per Transwell) were then added to the wells aseptically directly before the FUS treatment.…”

“…Here we developed a sporadic AD patient-derived BBB-like in vitro model to study the effects of FUS +MB on cellular responses and drug delivery. We utilized APOE3- and APOE4- carrying BBB cells and investigated molecular changes following FUS +MB as well as the FUS +MB -mediated delivery of two therapeutic AD antibodies: an Aducanumab analogue (anti-Aβ antibody, commercially known as Aduhelm TM ) [24, 25], and RNF5, an anti-Tau antibody, which has recently been shown to be efficient in reducing p-Tau levels in an animal model with Tau pathology [26]. Here, we report the improved delivery of these antibodies in our BBB-like in vitro model using FUS +MB and the cell-specific effects FUS +MB confers in an APOE3 / APOE4 context.…”