Anti-Tau Monoclonal Antibodies Derived from Soluble and Filamentous Tau Show Diverse Functional Properties in vitro and in vivo

Abstract

The tau spreading hypothesis provides rationale for passive immunization with an anti-tau monoclonal antibody to block seeding by extracellular tau aggregates as a disease-modifying strategy for the treatment of Alzheimer's disease (AD) and potentially other tauopathies. As the biochemical and biophysical properties of the tau species responsible for the spatio-temporal sequences of seeding events are poorly defined, it is not yet clear which epitope is preferred for obtaining optimal therapeutic efficacy. Our internal tau antibody collection has been generated by immunizations with different tau species: aggregated- and non-aggregated tau and human postmortem AD brain-derived tau fibrils. In this communication, we describe and characterize a set of these anti-tau antibodies for their biochemical and biophysical properties, including binding, tissue staining by immunohistochemistry, and epitope. The antibodies bound to different domains of the tau protein and some were demonstrated to be isoform-selective (PT18 and hTau56) or phospho-selective (PT84). Evaluation of the antibodies in cellular- and in vivo seeding assays revealed clear differences in maximal efficacy. Limited proteolysis experiments support the hypothesis that some epitopes are more exposed than others in the tau seeds. Moreover, antibody efficacy seems to depend on the structural properties of fibrils purified from tau Tg mice- and postmortem human AD brain.

Highly specific and selective anti‐pS396‐tau antibody C10.2 targets seeding‐competent tau

“…In light of failed clinical trials using small molecules to inhibit tau phosphorylation (glycogen synthase kinase 3 inhibitor [41]) or aggregation (leuco‐methylthioninium bis [42]), immunotherapy targeting the propagation of tau pathology offers an attractive new endeavor to treat AD. Recent studies highlight differences in neutralization efficiency of tau seeds by a panel of antibodies, suggesting that not all tau epitopes present optimal targets for immunotherapy [30]. Seeding and spreading is believed to be an ongoing process in the AD brain and our data indicate that C10.2 would specifically target tau seeds and neutralize these when present in the extracellular space.…”

“…By this procedure, three clones were generated (C10.2, C10.1 from C57/BL6, and D1.2 from FVB mice) and characterized in subsequent range of assays. In addition, the following antibodies were included: PHF13 (tau-p396, Thermo Fisher Scientific); AT8 (tau-p202/p205, Thermo Fisher Scientific); Tau 5 (total tau, Thermo Fisher Scientific); E1 (human-specific tau (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33), generated in rabbit [32].…”

“…Active vaccination studies with tau peptides indicated that raising an immune response against specific phosphorylated epitopes of tau could prevent the formation of tau pathology in tau transgenic mouse models [15][16][17][18][19][20]. Subsequently, passive immunization with different phospho-dependent and phospho-independent tau antibodies was reported to reduce tau pathology in different tau transgenic mouse models [21][22][23][24][25][26][27][28][29][30][31]. In this report, we describe the generation of pS396-tau specific antibodies and demonstrate in vitro and in vivo evidence that suggest anti-pS396 antibodies have a therapeutic potential to prevent seeding of tau pathology.…”

From the prion-like propagation hypothesis to therapeutic strategies of anti-tau immunotherapy

“…In this regard, Clavaguera and co-workers showed that injecting tau aggregates extracted from mice overexpressing mutated tau (P301S) into mice overexpressing human wild-type tau was sufficient to induce tau pathology [45]. When a tauimmunodepleted extract is injected, no pathology can be detected, showing that tau is the responsible factor as confirmed later by other groups [134,179,194]. However, this seeding activity may also require the presence of different co-factors such as polyanions [58,201].…”

“…It also effectively prevented the induction of tau pathology in the brain of transgenic mice injected with human AD brain extracts, in contrast to an amino-terminal tau antibody recognizing the same epitope as BIIB092 [2]. Other antibodies have also been tested by Vandermeeren and collaborators from Janssen [179]. Immunodepletion assays strongly suggest that difference exist between epitopes.…”