A pan-strain therapeutic tau antibody prevents seeded aggregation induced by multiple human tauopathies
Angers R1, Courade JP1, Mairet-Coello G1, Pacico N1, Mushikiwabo ML1, Schmitt M1, Deprez T1, Hustadt F1, Frequin JM1, De Wolf C1, Caruso M1, Westwood M2, Nan R2, Baker T2, McMillan D2, Griffin R2, Munro R2, Lightwood D2, Starkie D2, Odede G2, Sweeney B2, Michel A1, Popplewell A2, Tyson K2, Burgess G2,3, Downey P1, Citron M1
1UCB Biopharma, Chemin du Foriest, 1420 Braine l'Alleud, Belgium; 2UCB Celltech, 208 Bath Road., Slough SL1 3WE, United Kingdom; 3Current affiliation: Vertex Pharmaceuticals, United Kingdom
A growing body of evidence suggests the stereotypical development of tau pathology along interconnected axonal tracts in Alzheimer's disease (AD) may result from the cell to cell transfer of assembled, extracellular tau species. An antibody capable of binding and neutralizing extracellular tau aggregates could therefore hold therapeutic potential in AD and other human tauopathies. As the optimal tau epitopes required for antibody activity were unknown, we initiated a large-scale immunization campaign utilizing a variety of immunogens and selected the most promising candidates based on functional neutralization of human AD tau seeds in a cell assay of seeded aggregation. The most promising antibody recognized a central epitope and exhibited full neutralization of tau seeds from three distinct human tauopathies (AD, progressive supranuclear palsy (PSP), and frontotemporal dementia (FTD)) with IC50 values in single digit nanomolar range. Peripheral administration of the lead antibody candidate in a transgenic mouse model of tau spread also resulted in decreased pathology in regions distal to the injection site. Surprisingly, although antibodies clustered at the amino terminus of tau exhibited favorable binding kinetics to recombinant and AD-PHF tau, they failed to robustly neutralize extracellular tau seeds in our cell assay suggesting epitope, rather than affinity, as the major determinant of antibody efficacy.