Timing matters: early administration of a high-affinity antibody targeting the tau repeat domain prevents aggregation in a mouse tauopathy model

Introduction: Immunotherapy is an attractive proposition for preventing the spread of pathologic tau in Alzheimer’s disease and other tauopathies. Given that tau is heavily truncated in tauopathies, it is hypothesised that directly targeting the repeat domain which forms the core of pathological filaments will improve the likelihood of success. S1D12, a chimeric IgG2a isolated via phage display, recognises 2N4R tau341-353 with high affinity (200 pM) and has previously been shown to prevent tau aggregation and propagation in vitro. We further explored the pharmacokinetics and biodistribution of S1D12 as well as its efficacy in a tauopathy mouse model. We also verified its efficacy in vitro against tau seeding species from multiple human tauopathies.

Methods: Single dose S1D12 intraperitoneal injections (30 mg/kg) were performed in wild-type mice followed by tissue harvest at multiple time points. For efficacy studies, four-weekly doses followed by four-fortnightly doses of S1D12 (30 mg/kg) or negative control antibody were administered intraperitoneally to Line 66 tau transgenic mice. Two cohorts, beginning from 2 months and 4.5 months of age were utilised. Endpoints included quantification of aggregated tau, seed-competent tau and insoluble phosphorylated tau in brain homogenates, as well as neurofilament light (NfL), tau phosphorylated at Thr-217 (pTau217) and core tau in plasma.

Results: S1D12 was detected in plasma and in brain with a tmax of 24/48 h respectively, and a slow washout over 7 days (t1/2 > 230 h), with 0.35% CNS bioavailability. S1D12 inhibited the generation of aggregated tau, seed-competent tau and insoluble phosphorylated tau in transgenic mice. This was associated with a reduction in NfL and pTau217, and an increase in core tau in plasma. In the 4.5-month cohort, S1D12 did not remove already established tau aggregates below baseline. Additionally, S1D12 inhibited seeding tau species from different tauopathies to a similar degree, independent of structural diversity.

Conclusions: S1D12, a high-affinity antibody targeting the R4 repeat domain of tau offers potential for halting progression of tau pathology through inhibition of tau aggregation rather than removal of established aggregates. These findings support the notion that both early diagnosis and intervention are key for the treatment of AD and other tauopathies.