タウ蛋白ターゲットの治療薬開発の展望

抄録

Tau is well established as a microtubule–associated protein in neurons. However, under pathological conditions, aberrant post–translational modifications of tau such as phosphorylation cause tau protein to detach the microtubules. In recent years, clinical trials of tau targeting drugs such as immunotherapy, phosphorylation inhibitor and microtubule stabilizer have been conducted. Three phase II clinical trials on active and passive tau immunizations are being carried out. AADvac–1 is a vaccine using a KLH–conjugated peptide of second microtubule binding domain. This vaccine inhibits tau recombinant oligomerization and decreases tau phosphorylation in tau transgenic mice. C2N8E12 is a humanized monoclonal antibody which binds 4 microtubule–binding domains, consisting of 4 conserved sequence repeats. In vitro cell study showed that C2N8E12 was able to interrupt the cellular tau propagation. In tau transgenic mice, intraventricular injection of C2N8E12 inhibited cognitive dysfunction and decreased the number of phosphorylated tau–positive neurons. BMS–986168 is a humanized monoclonal antibody which was raised against extracellular tau, eTau. Previously, eTau had been affinity purified from Alzheimer's disease patient–derived cortical neuron conditioned media. Two Phase I studies on active and passive immunization are also being conducted. ACI–35 is a liposome–based vaccine which would recognize phosphor–serine–396 and –404. RO7105705 antibody against phosphor–serine–409 was modulated by mutations in the immunoglobulin G Fc region to reduce effector function. In terms of tau–aggregation inhibitor, the primary analysis of phase III clinical trial of TRx0327 did not suggest benefit as an add–on treatment for patients with mild to moderate Alzheimer's disease (AD). With regard to microtubule–stabilizing drug, TPI287 which crosses the blood–brain barrier is also being clinically developed at phase I. As for tau phosphorylation inhibitor, meta–analysis of 3 randomized placebo–controlled trials of lithium with AD and mild cognitive impairment revealed lithium may have beneficial effects on cognitive performance.