Research ArticleALZHEIMERS DISEASE

Antibody semorinemab reduces tau pathology in a transgenic mouse model and engages tau in patients with Alzheimer’s disease

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Science Translational Medicine  12 May 2021:
Vol. 13, Issue 593, eabb2639
DOI: 10.1126/scitranslmed.abb2639

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Developing an immunotherapy for AD

Hyperphosphorylated TAU aggregates contribute to neurodegeneration in patients with Alzheimer’s disease (AD), and reducing TAU accumulation had therapeutic effects in preclinical models. Here, Ayalon et al. generated and characterized a humanized anti-TAU monoclonal antibody, called semorinemab, and tested it in mice, nonhuman primates, and in a phase 1 clinical trial in humans. Semorinemab was able to bind all six human tau isoforms and had therapeutic effects in vivo in AD mice, by reducing TAU accumulation. In patients with AD, semorinemab crossed the blood-brain barrier and showed evidence of target engagement, without evident side effects. The results support the idea that immunotherapies targeting TAU might be effective in reducing TAU pathology in AD.

Abstract

Tau has become an attractive alternative target for passive immunotherapy efforts for Alzheimer’s disease (AD). The anatomical distribution and extent of tau pathology correlate with disease course and severity better than other disease markers to date. We describe here the generation, preclinical characterization, and phase 1 clinical characterization of semorinemab, a humanized anti-tau monoclonal antibody with an immunoglobulin G4 (igG4) isotype backbone. Semorinemab binds all six human tau isoforms and protects neurons against tau oligomer neurotoxicity in cocultures of neurons and microglia. In addition, when administered intraperitoneally once weekly for 13 weeks, murine versions of semorinemab reduced the accumulation of tau pathology in a transgenic mouse model of tauopathy, independent of antibody effector function status. Semorinemab also showed clear evidence of target engagement in vivo, with increases in systemic tau concentrations observed in tau transgenic mice, nonhuman primates, and humans. Higher concentrations of systemic tau were observed after dosing in AD participants compared to healthy control participants. No concerning safety signals were observed in the phase 1 clinical trial at single doses up to 16,800 mg and multiple doses totaling 33,600 mg in a month.

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